CN102690221A - Modified lysine-mimetic compounds - Google Patents

Modified lysine-mimetic compounds Download PDF

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Publication number
CN102690221A
CN102690221A CN2012101068106A CN201210106810A CN102690221A CN 102690221 A CN102690221 A CN 102690221A CN 2012101068106 A CN2012101068106 A CN 2012101068106A CN 201210106810 A CN201210106810 A CN 201210106810A CN 102690221 A CN102690221 A CN 102690221A
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compound
tetramethyleneimine
benzamido
amino
formic acid
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CN2012101068106A
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CN102690221B (en
Inventor
B·D·拉尔森
J·S·彼得森
K·J·豪根
J·A·布图拉
J·K·亨纳
E·H·科恩斯
E·L·皮亚特尼特斯基
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Zealand Pharma AS
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Zealand Pharma AS
Wyeth LLC
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Abstract

The invention relates to a modified lysine-mimetic compounds. Lysine mimetic compounds having useful pharmacological activity such as antiarrhythmic activity and desirable bioavailability properties are disclosed.

Description

The lysine-mimetic compounds of modification
The application be submitted on December 21st, 2006, denomination of invention divides an application for the PCT application PCT/US2006/048790's of " lysine-mimetic compounds of modification "; It is on July 25th, 2008 that said PCT application gets into the date in China national stage, and application number is 200680051855.0.
Technical field
The present invention relates to lysine-mimetic compounds (lysine mimetic compound), it has pharmacological activity, like antiarrhythmic activity, and the ideal bioavailability.The invention still further relates to the pharmaceutical composition that comprises this compounds, and use and prepare this compounds and method for compositions.
Background technology
The running balance of cell-cell communication pair cell, propagation and differentiation are indispensable, and this point is gradually by cognition.It is believed that this exchanging meeting is connected promotion by the gap.These structures are considered to the passage of coupling cell and permission " interchange (cross-talk) each other ".(usually can be referring to Sperelakis N., editor., Cell Interactions and Gap Junctions (cell interaction and gap connect), CRC Press, Inc. (1989)).Mutual interchange between the gap connects is called as " gap connectivity cell-cell communication " (GJIC).
Usually, it is the specialization zone of cytolemma that the gap connects, and it contains the clump bunch of hundreds of passages to thousands of tight hematocrits, and this passage directly connects the tenuigenin of two flanking cells.The gap connecting passage comprises two hemichannels or connexon (connexon), and it is provided by two flanking cells separately.Each connexon is called as the proteic protein of connection by six again and forms.
In heart, the conduction of electricimpulse connects generation through the gap.Unusual GJIC and various disease states comprise that heart trouble is relevant.For example, pointed out the mouse of Cx43 gene (the specific ventricle of encoding connects proteic gene) heterozygosis, manifested spontaneous ventricular arrhythmia and suffer sudden cardiac death (people such as Guerrero, J.Clin.Invest., 99,1991-1998 (1997)).The occurrence frequency increase of ventricular arrhythmia has direct relation during reduction that Cx43 expresses in the heterozygosis mouse and the local asphyxia.(people such as Lerner, Circulation, 101,547-552 (2000)).Some other researchs point out, and the expression of Cx43 reduces or distribute and change (people such as Kaprelian, Circulation, 97,651-660 (1998) in chronic local asphyxia, dormancy or loose heart; People such as Peters, Circulation, 88,864-875 (1993); People such as Saffitz, Cardiovasc.Res., 42,309-317 (1999)).
Identify the some peptides that influence GJIC, comprised antiarrhythmia peptide AAP (people such as Aonuma, Chem.Pharm.Bull. (Tokyo); 28,3332-3339 (1980)), AAP10 (people such as Dhein; Naunyn Schmiedebergs Arch Pharmacol., 350,174-184 (1994); People such as Muller, Eur.J.Pharmacol., 327,65-72 (1997)), and HP5 (being disclosed in USP the 4th, 775, No. 743).Yet these peptides have unfavorable characteristic, comprise low stability, short-half-life and lack oral administration biaavailability.
Summary
In broad terms, the present invention relates to have useful pharmacological activity, like the lysine-mimetic compounds of antiarrhythmic activity and ideal bioavailability characteristics.The present invention provides common compound and pharmaceutically-acceptable salts class, ester, hydrate and prodrug by formula I representative:
Figure BDA0000152435510000021
Wherein Y is OX, OR 2, NXR 2Or NR 2R 3K is 0,1 or 2; X is H or lysine-mimetic; X ' is OR 3, NR 2R 3Or lysine-mimetic; R 1Be H, optional substituted C 1-10Alkyl, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl or amino acid side chain; And R 2And R 3As defined herein.
According to the specific examples of compound of the present invention comprise 4-amino-tetramethyleneimine-2-formic acid with formula II or formula III (4-aminoproline, 4Amp) analogue and pharmacy acceptable salt thereof, ester, hydrate and prodrug:
Figure BDA0000152435510000031
Wherein A, B, E, k, R 1, R 4, R 5, Y ', Z and Z ' be as defined herein.
Description of drawings
Fig. 1 shows the experimental result of research compound in emergent atrium delayed conduction that brings out of metabolism and effect in external model (people such as Haugan is described in J.Cardiovasc.Electrophysiol., 16,537-545 (2005)).
Summary of the invention
On the one hand, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug by formula I representative:
Wherein:
Y is selected from OX, OR 2, NXR 2And NR 2R 3
K is 0,1 or 2;
X is H or lysine-mimetic;
X ' is selected from OR 3, NR 2R 3And lysine-mimetic;
R 1Be selected from H, optional substituted C 1-10Alkyl, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl and amino acid side chain;
R 2And R 3Be selected from H, optional substituted C independently of one another 1-10Alkyl, optional substituted C 3-20Naphthenic base, optional substituted C 7-20Aralkyl, optional substituted C 6-20Aryl, the first Heterocyclylalkyl of optional substituted 3-20, the first heteroaryl of optional substituted 5-20, C (O) R 6, C (O) OR 6, C (O) NR 6R 7, S (O) 2R 6And S (O) 2NR 6R 7
Perhaps, R 2And R 3Form 3-20 unit heterocycle with their institute's bonded nitrogen-atoms, said heterocycle is chosen wantonly to contain 1-4 ring hetero atom (this ring hetero atom is independently selected from O, N and S) and choose wantonly by 1-5 Q base and is replaced;
R 6And R 7Be selected from H, optional substituted C independently of one another 1-10Alkyl, optional substituted C 3-20Naphthenic base, optional substituted C 2-10Thiazolinyl, optional substituted C 2-10Alkynyl, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl, the first Heterocyclylalkyl of optional substituted 3-20, the first heteroaryl of optional substituted 5-20, C (O) R 8, C (O) OR 8And C (O) NR 8R 9
Perhaps, R 6And R 7Form 3-20 unit heterocycle with their institute's bonded nitrogen-atoms, said heterocycle is chosen wantonly to contain 1-4 ring hetero atom (this ring hetero atom is independently selected from O, N and S) and choose wantonly by 1-5 Q base and is replaced;
R 8And R 9Be selected from H, optional substituted C independently of one another 1-10Alkyl, optional substituted C 3-20Naphthenic base, optional substituted C 2-10Thiazolinyl, optional substituted C 2-10Alkynyl, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl, optional substituted 3-20 unit's Heterocyclylalkyl and the first heteroaryl of optional substituted 5-20;
The each appearance of Q all is independently selected from optional substituted C 1-10Alkyl, optional substituted C 2-10Thiazolinyl, optional substituted C 2-10Alkynyl, optional substituted C 3-20Naphthenic base, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl, the first Heterocyclylalkyl of optional substituted 3-20, the first heteroaryl of optional substituted 5-20, F, Cl, Br, I, CN, CF 3, OCF 3, NO 2, OR 8, SR 8, S +R 8 2, S (O) R 8, S (O) 2R 8, S (O) 2OH, S (O) 2NR 8R 9, NR 8S (O) 2R 9, C (O) R 8, C (O) OR 8, C (O) NR 8R 9, OC (O) R 8, NR 8R 9, NR 8C (O) R 9, NR 8C (O) OR 9, NR 8C (O) NR 8R 9And N +R 8 3
Condition is:
A) when Y be OX or NXR 2And when X was H, X ' was a lysine-mimetic;
B) when Y be OR 2Or NR 2R 3The time, X ' is a lysine-mimetic; And
C) compound is not 1-(the amino propionyl group of 2-)-4-benzamido-tetramethyleneimine-2-formic acid or 1-(the amino propionyl group of 2-)-4-benzene carbon amide phenylpiperidines-2-formic acid.
Embodiments more of the present invention comprise compound and pharmacy acceptable salt, ester, hydrate and prodrug, and wherein Y is OX or NXR 2, X ' is OR 3Or NR 2R 3, and X is lysine-mimetic, wherein said lysine-mimetic is selected from:
Figure BDA0000152435510000051
Wherein:
Z ' is selected from H, (CH 2) m-C 6-20Aryl, (CH 2) m-5-20 unit heteroaryl, C (O) (CH 2) m-C 6-20Aryl, C (O) (CH 2) m-5-20 unit heteroaryl, (CH 2) mC (O)-C 6-20Aryl, (CH 2) mC (O)-5-20 unit heteroaryl, S (O) 2(CH 2) m-C 6-20Aryl and S (O) 2(CH 2) m-5-20 unit heteroaryl, wherein each C 6-20Aryl and 5-20 unit heteroaryl are optional to be replaced by 1-5 Q base;
R 5Be H or optional substituted C 1-10Alkyl;
M is 0,1 or 2; And
Q, R 2And R 3Such as preceding text definition.
In other embodiments, Y is OR 2, NR 2R 3, OX or NXR 2, X is H, and X ' is lysine-mimetic, wherein said lysine-mimetic is selected from:
Figure BDA0000152435510000061
Wherein:
Z ' is selected from H, (CH 2) m-C 6-20Aryl, (CH 2) m-5-20 unit heteroaryl, C (O) (CH 2) m-C 6-20Aryl, C (O) (CH 2) m-5-20 unit heteroaryl, (CH 2) mC (O)-C 6-20Aryl, (CH 2) mC (O)-5-20 unit heteroaryl, S (O) 2(CH 2) m-C 6-20Aryl and S (O) 2(CH 2) m-5-20 unit heteroaryl, wherein each C 6-20Aryl and 5-20 unit heteroaryl are optional to be replaced by 1-5 Q base;
R 5Be H or optional substituted C 1-10Alkyl;
M is 0,1 or 2;
E is selected from C (O) OR 6, C (O) NR 6R 7And carboxylic acid bioisostere; And
Q, R 2, R 3, R 6And R 7Such as preceding text definition.
In some examples of these embodiments, E is C (O) OH.In other example, E is C (O) NR 6R 7(C (O) NHR for example 7Or C (O) NH 2).
In any compound of the present invention, Z ' can be optional by 1-5 substituted C (the O) (CH of Q base institute 2) m-C 6-20Aryl, and m can be 0.For example, Z ' can be benzoyl-.
In some embodiments of compound of the present invention, R 1Be H.In other embodiments, R 1Be amino acid side chain.R 1The example of suitable amino acid side chain can include, but is not limited to Xie Ansuan, norvaline, leucine, nor-leucine, Isoleucine, methionine(Met), L-Ala, phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine, halfcystine, Methionin, l-arginine, Histidine, aspartic acid, L-glutamic acid, l-asparagine, Stimulina, ornithine, 2; 4-DAB and 2, the 6-diaminopimelic acid.
In some embodiments, k is 0; In other embodiments, k is 1.
Specific compound of the present invention has the structure by following formula I (a)-I (p) representative, and wherein X ' is OR 3(for example OH) or NR 2R 3(NH for example 2), Y is OR 2(for example OH) or NR 2R 3(NH for example 2), E is C (O) OR 6Or C (O) NR 6R 7, and R 1, R 2, R 3, R 5, R 6, R 7And Z ' is as defined herein:
Figure BDA0000152435510000081
Figure BDA0000152435510000091
Some compound of the present invention has the structure by following formula I (q)-I (x) representative, wherein R 1, R 2, E and each R 5And Z ' (its each can be identical or different) is as defined herein:
Figure BDA0000152435510000101
Figure BDA0000152435510000111
In some embodiments, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug of formula I, and wherein X ' is OR 3Or NR 2R 3(for example OH or NH 2), Y is NXR 2, X does
Figure BDA0000152435510000121
And Z ', k, R 1, R 2, R 3And R 5Such as preceding text definition.In some examples of these compounds, Z ' is for choosing wantonly by 1-5 Q base substituted C (the O) (CH of institute 2) m-C 6-20Aryl, and m is 0 (for example Z ' can be benzoyl-).In some compounds, R 1Be H.In other compound, R 1Be amino acid side chain, wherein said amino acid is selected from Xie Ansuan, leucine, Isoleucine, methionine(Met), L-Ala, phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine, halfcystine, Methionin, l-arginine, Histidine, aspartic acid, L-glutamic acid, l-asparagine and Stimulina.In some compounds, k is 0; In other compound, k is 1.Specific examples according to the compound of these embodiments of the present invention includes, but is not limited to 3-[(4-benzoyl-amido-tetramethyleneimine-2-carbonyl)-amino]-propionic acid; { [4-(4-nitro-benzoyl-amido)-tetramethyleneimine-2-carbonyl]-amino }-acetate; { [4-(4-methoxyl group-benzoyl-amido)-tetramethyleneimine-2-carbonyl]-amino }-acetate; 2-[(4-benzoyl-amido-tetramethyleneimine-2-carbonyl)-amino]-succinamic acid; 2-[(4-benzoyl-amido-tetramethyleneimine-2-carbonyl)-amino]-3-phenyl-propionic acid; 2-[(4-benzoyl-amido-tetramethyleneimine-2-carbonyl)-amino]-4-methyl-valeric acid; 6-amino-2-(4-benzamido-tetramethyleneimine-2-formamido group) caproic acid; [(4-benzoyl-amido-tetramethyleneimine-2-carbonyl)-amino]-acetate; { [4-benzoyl-amido-piperidines-2-carbonyl]-amino }-acetate; { [4-benzoyl-amido-piperidines-2-carbonyl]-amino }-propionic acid and pharmacy acceptable salt thereof; Ester; Hydrate and prodrug.
In certain embodiments, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug of formula I, and wherein X ' is OR 3Or NR 2R 3(for example OH or NH 2), Y is NXR 2, X does
And Z ', k, R 1, R 2, R 3And R 5Such as preceding text definition.In some examples of these compounds, Z ' is for choosing wantonly by 1-5 Q base substituted C (the O) (CH of institute 2) m-C 6-20Aryl, and m is 0 (for example Z ' can be benzoyl-).In some compounds, R 1Be H.In other compound, R 1Be amino acid side chain, wherein said amino acid is selected from Xie Ansuan, leucine, Isoleucine, methionine(Met), L-Ala, phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine, halfcystine, Methionin, l-arginine, Histidine, aspartic acid, L-glutamic acid, l-asparagine and Stimulina.In some compounds, k is 0; In other compound, k is 1.Specific example according to the compound of these embodiments of the present invention includes, but is not limited to 3-amino-5-benzoyl-amido-benzoyl-amido)-acetate, (3-amino-5-(4-methoxyl group-benzoyl-amido)-benzoyl-amido)-acetate, (3-amino-5-(4-methyl-benzoyl-amido)-benzoyl-amido)-acetate, (3,5-diamino--benzoyl-amido)-acetate and pharmacy acceptable salt, ester, hydrate and prodrug.
In some embodiments, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug of formula I, and wherein X ' is OR 3Or NR 2R 3(for example OH or NH 2), Y is NXR 2, X does
Figure BDA0000152435510000132
And Z ', k, R 1, R 2And R 3Such as preceding text definition.In some examples of these compounds, Z ' is for choosing wantonly by 1-5 Q base substituted C (the O) (CH of institute 2) m-C 6-20Aryl, and m is 0 (for example Z ' can be benzoyl-).In some compounds, R 1Be H.In other compound, R 1Be amino acid side chain, wherein said amino acid is selected from Xie Ansuan, leucine, Isoleucine, methionine(Met), L-Ala, phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine, halfcystine, Methionin, l-arginine, Histidine, aspartic acid, L-glutamic acid, l-asparagine and Stimulina.In some compounds, k is 0; In other compound, k is 1.Specific example according to the compound of these embodiments of the present invention includes, but is not limited to [(1-benzoyl--imidazolidine-2-carbonyl)-amino] acetate, { [1-(4-nitro-benzoyl-)-imidazolidine-2-carbonyl]-amino } acetate and pharmacy acceptable salt, ester, hydrate and prodrug.
In certain embodiments, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug of formula I, and wherein X ' is OR 3Or NR 2R 3(for example OH or NH 2), Y is NXR 2, X does
Figure BDA0000152435510000141
And Z ', k, R 1, R 2, R 3And R 5Such as preceding text definition.In some examples of these compounds, Z ' is for choosing wantonly by 1-5 Q base substituted C (the O) (CH of institute 2) m-C 6-20Aryl, and m is 0 (for example Z ' can be benzoyl-).In some compounds, R 1Be H.In other compound, R 1Be amino acid side chain, wherein said amino acid is selected from Xie Ansuan, leucine, Isoleucine, methionine(Met), L-Ala, phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine, halfcystine, Methionin, l-arginine, Histidine, aspartic acid, L-glutamic acid, l-asparagine and Stimulina.In some compounds, k is 0; In other compound, k is 1.Specific example according to the compound of these embodiments of the present invention includes, but is not limited to [2-amino-3-(4-benzoyl-amido-phenyl)-propionyl group is amino]-acetate; 2-{2-amino-3-[4-(the 4-methoxybenzoyl is amino) phenyl] propionamido } acetate; 2-{2-amino-3-[4-(4-nitrobenzoyl amido) phenyl] propionamido } acetate; 2-{2-amino-3-[4-(the 4-toluyl is amino) phenyl] propionamido } acetate and pharmacy acceptable salt thereof; Ester; Hydrate and prodrug.
In some embodiments, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug of formula I, and wherein X ' is OR 3Or NR 2R 3(for example OH or NH 2), Y is NXR 2, X does
Figure BDA0000152435510000151
And Z ', k, R 1, R 2And R 3Such as preceding text definition.In some examples of these compounds, Z ' is for choosing wantonly by 1-5 Q base substituted C (the O) (CH of institute 2) m-C 6-20Aryl, and m is 0 (for example Z ' can be benzoyl-).In some compounds, R 1Be H.In other compound, R 1Be amino acid side chain, wherein amino acid is selected from Xie Ansuan, leucine, Isoleucine, methionine(Met), L-Ala, phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine, halfcystine, Methionin, l-arginine, Histidine, aspartic acid, L-glutamic acid, l-asparagine and Stimulina.In some compounds, k is 0; In other compound, k is 1.Specific example according to the compound of these embodiments of the present invention includes, but is not limited to [(4-amino-1-benzoyl-piperidine-4-carbonyl)-amino]-acetate and pharmacy acceptable salt, ester, hydrate and prodrug.
In certain embodiments, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug of formula I, and wherein Y is OR 2Or NR 2R 3, X ' does
Figure BDA0000152435510000152
And Z ', k, E, R 1, R 2, R 3And R 5Such as preceding text definition, condition is that said compound is not 1-(2-amino propionyl group)-4-benzene carbon amide phenylpiperidines-2-formic acid.In some examples of these embodiments, Y is OH or NH 2In some compounds, E is C (O) OR 6(for example C (O) OH) or C (O) NR 6R 7(C (O) NHR for example 7Or C (O) NH 2).In some compounds, Z ' is for choosing wantonly by 1-5 Q base substituted C (the O) (CH of institute 2) m-C 6-20Aryl, and m is 0 (for example Z ' is a benzoyl-).In some compounds, R 1Be H.In other compounds, R 1Be amino acid side chain, wherein said amino acid is selected from Xie Ansuan, leucine, Isoleucine, methionine(Met), L-Ala, phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine, halfcystine, Methionin, l-arginine, Histidine, aspartic acid, L-glutamic acid, l-asparagine and Stimulina (condition is that compound is not 1-(the amino propionyl group of 2-)-4-benzene carbon amide phenylpiperidines-2-formic acid).In some compounds, k is 0; In other compound, k is 1.Specific example according to the compound of these embodiments of the present invention includes, but is not limited to 1-(2-amino-4-carboxyl-butyryl radicals)-4-benzoyl-amido-piperidines-2-formic acid, 1-(2-amino-4-methyl-pentanoyl)-4-benzoyl-amido-piperidines-2-formic acid, 4-benzoyl-amido-1-(2,6-diamino--caproyl)-piperidines-2-formic acid, 1-(2-amino-ethanoyl)-4-benzoyl-amido-piperidines-2-formic acid, 1-(3-amino-propionyl group)-4-benzoyl-amido-piperidines-2-formic acid, 1-[2-amino-3-(1H-indol-3-yl)-propionyl group]-4-benzoyl-amido-piperidines-2-formic acid, 1-(2-amino-3-phenyl-propionyl group)-4-benzoyl-amido-piperidines-2-formic acid, 4-benzoyl-amido-1-(2-hydroxyl-ethanoyl)-piperidines-2-formic acid and pharmacy acceptable salt, ester, hydrate and prodrug.
In some embodiments, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug of formula I, and wherein Y is OR 2Or NR 2R 3, X ' does
Figure BDA0000152435510000161
And Z ', k, E, R 1, R 2And R 3Such as preceding text definition.In some examples of these embodiments, Y is OH or NH 2In some compounds, E is C (O) OR 6(for example C (O) OH) or C (O) NR 6R 7(C (O) NHR for example 7Or C (O) NH 2).In some compounds, Z ' is for choosing wantonly by 1-5 Q base substituted C (the O) (CH of institute 2) m-C 6-20Aryl, and m is 0 (for example Z ' is a benzoyl-).In some compounds, R 1Be H.In other compound, R 1Be amino acid side chain, wherein said amino acid is selected from Xie Ansuan, leucine, Isoleucine, methionine(Met), L-Ala, phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine, halfcystine, Methionin, l-arginine, Histidine, aspartic acid, L-glutamic acid, l-asparagine and Stimulina.In some compounds, k is 0; In other compound, k is 1.Specific example according to the compound of these embodiments of the present invention includes, but is not limited to 1-(2-amino-4-carboxyl-butyryl radicals)-3-benzoyl--imidazolidine-2-formic acid, 1-benzoyl--3-(2-hydroxyl-ethanoyl)-imidazolidine-2-benzoic acid amides, 1-benzoyl--3-(2-hydroxyl-ethanoyl)-imidazolidine-2-formic acid and pharmacy acceptable salt, ester, hydrate and prodrug.
In certain embodiments, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug of formula I, and wherein Y is OR 2Or NR 2R 3, X ' does
Figure BDA0000152435510000171
And Z ', k, E, R 1, R 2, R 3And R 5Such as preceding text definition.In some examples of these embodiments, Y is OH or NH 2In some compounds, E is C (O) OR 6(for example C (O) OH) or C (O) NR 6R 7(C (O) NHR for example 7Or C (O) NH 2).In some compounds, Z ' is for choosing wantonly by 1-5 Q base substituted C (the O) (CH of institute 2) m-C 6-20Aryl, and m is 0 (for example Z ' is a benzoyl-).In some compounds, R 1Be H.In other compound, R 1Be amino acid side chain, wherein said amino acid is selected from Xie Ansuan, leucine, Isoleucine, methionine(Met), L-Ala, phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine, halfcystine, Methionin, l-arginine, Histidine, aspartic acid, L-glutamic acid, l-asparagine and Stimulina.In some compounds, k is 0; In other compound, k is 1.Specific example according to the compound of these embodiments of the present invention includes, but is not limited to 3-benzoyl-amido-5-(2-hydroxyl-kharophen)-phenylformic acid, 3-(the 2-glycyl is amino)-5-benzene carbon amide yl benzoic acid, 3-(the 2-glycyl is amino)-5-(the 4-toluyl is amino) phenylformic acid, 3-(2-amino-3-formamyl-propionyl group is amino)-5-benzoyl-amido-phenylformic acid and pharmacy acceptable salt, ester, hydrate and prodrug.
In certain embodiments, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug of formula I, and wherein Y is OR 2Or NR 2R 3, X ' does
Figure BDA0000152435510000172
And Z ', k, E, R 1, R 2, R 3And R 5Such as preceding text definition.In some examples of these embodiments, Y is OH or NH 2In some compounds, E is C (O) OR 6(for example C (O) OH) or C (O) NR 6R 7(C (O) NHR for example 7Or C (O) NH 2).In some compounds, Z ' is for choosing wantonly by 1-5 Q base substituted C (the O) (CH of institute 2) m-C 6-20Aryl, and m is 0 (for example Z ' is a benzoyl-).In some compounds, R 1Be H.In other compound, R 1Be amino acid side chain, wherein said amino acid is selected from Xie Ansuan, leucine, Isoleucine, methionine(Met), L-Ala, phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine, halfcystine, Methionin, l-arginine, Histidine, aspartic acid, L-glutamic acid, l-asparagine and Stimulina.In some compounds, k is 0; In other compound, k is 1.Specific example according to the compound of these embodiments of the present invention includes, but is not limited to 3-(4-benzoyl-amido-phenyl)-2-(2-hydroxyl-kharophen)-propionic acid, N-{4-[2-formamyl-2-(2-hydroxyl-kharophen)-ethyl]-phenyl }-BM and pharmacy acceptable salt, ester, hydrate and prodrug.
In some embodiments, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug of formula I, and wherein Y is OR 2Or NR 2R 3, X ' does
And Z ', k, E, R 1, R 2And R 3Such as preceding text definition.In some examples of these embodiments, Y is OH or NH 2In some compounds, E is C (O) OR 6(for example C (O) OH) or C (O) NR 6R 7(C (O) NHR for example 7Or C (O) NH 2).In some compounds, Z ' is for choosing wantonly by 1-5 Q base substituted C (the O) (CH of institute 2) m-C 6-20Aryl, and m is 0 (for example Z ' is a benzoyl-).In some compounds, R 1Be H.In other compound, R 1Be amino acid side chain, wherein said amino acid is selected from Xie Ansuan, leucine, Isoleucine, methionine(Met), L-Ala, phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine, halfcystine, Methionin, l-arginine, Histidine, aspartic acid, L-glutamic acid, l-asparagine and Stimulina.In some compounds, k is 0; In other compound, k is 1.Specific example according to the compound of these embodiments of the present invention includes, but is not limited to 4-benzoyl-amido-1-(2-hydroxyl-kharophen)-cyclohexylenedinitrilotetraacetic acid, 4-(the 2-glycyl is amino)-1-benzoyl-piperidines-4-formic acid and pharmacy acceptable salt, ester, hydrate and prodrug.
The present invention includes all steric isomers of compound described herein.For example, the stereochemistry of dipeptides embodiment of the present invention can be 2R4R, 2R4S, 2S4S or 2S, 4R.
On the other hand, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug with formula II:
Figure BDA0000152435510000191
Wherein:
A is (CH 2) k-Y ';
K is 0,1 or 2;
Y ' is OR 2Or NR 2R 3
R 1Be selected from H, optional substituted C 1-10Alkyl, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl and amino acid side chain;
Perhaps, A and R 1Form 5-20 unit heteroaryl with its bonded carbon atom, this heteroaryl contains 1-4 ring hetero atom (this ring hetero atom is independently selected from N, O and S atom), and is optionally replaced by 1-5 Q is basic;
B is selected from NR 5, NR 5(CH 2) nC (O), NR 5(CH 2) nS (O) 2And acid amides bioisostere;
N is 0,1 or 2;
Z is selected from H, optional by 1-5 the substituted (CH of Q base 2) m-C 6-20Aryl and optional by 1-5 the substituted (CH of Q base 2) m-5-20 unit heteroaryl;
M is 0,1 or 2;
E is selected from C (O) OR 6, C (O) NR 6R 7, carboxylic acid bioisostere and acid amides bioisostere;
The each appearance of Q all is independently selected from optional substituted C 1-10Alkyl, optional substituted C 2-10Thiazolinyl, optional substituted C 2-10Alkynyl, optional substituted C 3-20Naphthenic base, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl, the first Heterocyclylalkyl of optional substituted 3-20, the first heteroaryl of optional substituted 5-20, F, Cl, Br, I, CN, CF 3, OCF 3, NO 2, OR 8, SR 8, S +R 8 2, S (O) R 8, S (O) 2R 8, S (O) 2OH, S (O) 2NR 8R 9, NR 8S (O) 2R 9, C (O) R 8, C (O) OR 8, C (O) NR 8R 9, OC (O) R 8, NR 8R 9, NR 8C (O) R 9, NR 8C (O) OR 9, NR 8C (O) NR 8R 9And N +R 8 3
R 2And R 3Be selected from H, optional substituted C independently of one another 1-10Alkyl, optional substituted C 3-20Naphthenic base, optional substituted C 7-20Aralkyl, optional substituted C 6-20Aryl, the first Heterocyclylalkyl of optional substituted 3-20, the first heteroaryl of optional substituted 5-20, C (O) R 6, C (O) OR 6, C (O) NR 6R 7, S (O) 2R 6And S (O) 2NR 6R 7
Perhaps, R 2And R 3Form 3-20 unit heterocycle with their institute's bonded nitrogen-atoms, said heterocycle is chosen wantonly to contain 1-4 ring hetero atom (this ring hetero atom is independently selected from O, N and S atom) and choose wantonly by 1-5 Q base and is replaced;
R 5Be hydrogen or optional substituted C 1-10Alkyl;
R 6And R 7Be selected from H, optional substituted C independently of one another 1-10Alkyl, optional substituted C 3-20Naphthenic base, optional substituted C 2-10Thiazolinyl, optional substituted C 2-10Alkynyl, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl, the first Heterocyclylalkyl of optional substituted 3-20, the first heteroaryl of optional substituted 5-20, C (O) R 8, C (O) OR 8And C (O) NR 8R 9
Perhaps, R 6And R 7Form 3-20 unit heterocycle with their institute's bonded nitrogen-atoms, said heterocycle is chosen wantonly to contain 1-4 ring hetero atom (this ring hetero atom is independently selected from O, N and S) and choose wantonly by 1-5 Q base and is replaced; And
R 8And R 9Be selected from H, optional substituted C independently of one another 1-10Alkyl, optional substituted C 3-20Naphthenic base, optional substituted C 2-10Thiazolinyl, optional substituted C 2-10Alkynyl, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl, optional substituted 3-20 unit's Heterocyclylalkyl and the first heteroaryl of optional substituted 5-20,
Condition is: said compound is not 1-(the amino propionyl group of 2-)-4-benzamido-tetramethyleneimine-2-formic acid.
In some embodiments, A is (CH 2) k-Y ' and Y ' are NR 2R 3The example of these embodiments comprises the compound as giving a definition: R wherein 2Be H and R 3Being selected from H (is that Y ' is NH 2), optional substituted C 1-10Alkyl, C (O) R 6And C (O) OR 6In some instances, A is (CH 2) k-Y ', Y ' are NR 2R 3, R 2Be H, R 3Be C (O) R 6And R 6Be H or optional substituted C 1-10Alkyl.In other example, A is (CH 2) k-Y ', Y ' are NR 2R 3, and R 2And R 3Independent of separately choosing substituted C wantonly 1-10Alkyl.In other embodiments, Y ' is OR 2And R 2Be H or C 1-10Alkyl.In arbitrary these embodiments, k can be 0,1 or 2.
In certain embodiments, A and R 1Form 5-20 unit heterocycle with its bonded carbon atom, this heterocycle contains 1-4 ring hetero atom (this ring hetero atom independently is selected from N, O and S), and chooses wantonly by 1-5 Q is basic and replace.The example of heterocyclic radical can include, but is not limited to piperidines, piperazine, morpholine, thiomorpholine, tetramethyleneimine,
Figure BDA0000152435510000211
azoles alkane, thiazolidine, imidazolidine, pyrroles, imidazoles, pyrazoles, triazole, tetrazolium, furans, thiophene,
Figure BDA0000152435510000212
azoles, different
Figure BDA0000152435510000213
azoles, thiazole, isothiazole, diazole, thiadiazoles, pyridine, pyridazine, pyrimidine, pyrazine, indoles, cumarone and thionaphthene, and it can be chosen wantonly separately and be substituted.The exemplary compounds of these embodiments includes, but is not limited to 4-benzamido--1-(1H-imidazoles-2-carbonyl) tetramethyleneimine-2-formic acid, 4-benzamido--1-(1H-pyrazoles-5-carbonyl) tetramethyleneimine-2-formic acid, and 4-benzamido--1-(1H-imidazoles-5-carbonyl) tetramethyleneimine-2-formic acid.
In some embodiments, B is NR 5(CH 2) nC (O), n are 0 (to be that B is NR 5C (O)), Z is for choosing wantonly by 1-5 the substituted C of Q base 6-20Aryl or optional by 1-5 substituted 5-20 unit of Q base institute heteroaryl.The example of these embodiments comprises the compound as giving a definition: R wherein 5Be H (being that B is NHC (O)).In some compounds, Z for optional by 1-5 Q base as, for instance, F, Cl, Br, I, C 1-10Alkyl, CF 3, OCF 3, NO 2, O-C 1-10Alkyl, OH, NH 2, NH (C 1-10Alkyl), N (C 1-10Alkyl) 2Or NHC (O) C 1-10The substituted phenyl of alkyl.In certain embodiments, B-Z is NHC (O)-phenyl.In some embodiments, Z is for choosing wantonly by 1-5 the substituted (CH of Q base 2) m-5-20 unit heteroaryl.In certain embodiments, m is 0.The exemplary compounds of these embodiments includes, but is not limited to 1-(2-glycyl)-4-(picoline amido) tetramethyleneimine-2-formic acid; 1-(2-glycyl)-4-(nicotinoyl is amino) tetramethyleneimine-2-formic acid; 1-(2-glycyl)-4-(different nicotinoyl is amino) tetramethyleneimine-2-formic acid; 1-(2-glycyl)-4-(pyrimidine-5-formamido group) tetramethyleneimine-2-formic acid; 1-(2-glycyl)-4-(the 2-fluorobenzoyl is amino) tetramethyleneimine-2-formic acid; 1-(2-glycyl)-4-(the 3-fluorobenzoyl is amino) tetramethyleneimine-2-formic acid; 1-(2-glycyl)-4-(the 4-fluorobenzoyl is amino) tetramethyleneimine-2-formic acid; 1-(2-glycyl)-4-(the 2-toluyl is amino) tetramethyleneimine-2-formic acid; 1-(2-glycyl)-4-(the 3-toluyl is amino) tetramethyleneimine-2-formic acid; 1-(2-glycyl)-4-(the 4-toluyl is amino) tetramethyleneimine-2-formic acid; 1-(2-glycyl)-4-(the 4-methoxybenzoyl is amino) tetramethyleneimine-2-formic acid; 1-(2-glycyl)-4-(the 3-methoxybenzoyl is amino) tetramethyleneimine-2-formic acid; 1-(2-glycyl)-4-(4-(2-hydroxybenzoyl) amino) tetramethyleneimine-2-formic acid and 1-(2-glycyl)-4-(3-(2-hydroxybenzoyl) amido) tetramethyleneimine-2-formic acid.
In some embodiments, B is NR 5(CH 2) nC (O), n are 0 (to be that B is NR 5C (O)) and Z for optional by 1-5 the substituted (CH of Q base 2) m-C 6-20Aryl, or optional by 1-5 the substituted (CH of Q base 2) m-5-20 unit heteroaryl, wherein m is 1 or 2.The non-limitative example of these embodiments is 1-(2-glycyl)-4-(2-phenyl kharophen) tetramethyleneimine-2-formic acid.In other embodiments, B is NR 5(CH 2) nC (O), wherein n is 1 or 2.The non-limitative example of these embodiments is 1-(2-glycyl)-4-(2-oxo-2-phenylethyl is amino) tetramethyleneimine-2-formic acid).
In other embodiments, B is NR 5, R 5Be H, Z is for choosing wantonly by 1-5 the substituted (CH of Q base 2) m-C 6-20Aryl or optional by 1-5 the substituted (CH of Q base 2) m-5-20 unit heteroaryl, and m is that 0 (for example 1-(2-glycyl)-4-(phenyl amino) tetramethyleneimine-2-formic acid) or m are 1 (for example 1-(2-glycyl)-4-(phenmethyl is amino) tetramethyleneimine-2-formic acid).In other other embodiments, B is NR 5(CH 2) nS (O) 2, n is 0 (to be that B is NR 5S (O) 2) and Z for optional by the basic substituted (CH of 1-5 Q 2) m-C 6-20Aryl or optional by 1-5 the substituted (CH of Q base 2) m-5-20 unit heteroaryl.A non-limitative example of these embodiments is 1-(2-glycyl)-4-(phenyl sulfonamido) tetramethyleneimine-2-formic acid).
In other other embodiment; B is the acid amides bioisostere; As; For instance; Imidazoles,
Figure BDA0000152435510000221
azoles, thiazole, pyrazoles, triazole, diazole, thiadiazoles or tetrazolium, it can be chosen wantonly separately and be substituted.Examples of these embodiments compounds include (but are not limited to) 1 - (2 - amino-acetyl) -4 - (4 - phenyl?
Figure BDA0000152435510000223
oxazol-2 - yl) pyrrolidine-2 - acid, 1 - (2 - amino- acetyl) -4 - (5 - phenyl?
Figure BDA0000152435510000224
oxazol-2 - yl) pyrrolidine-2 - carboxylic acid, 1 - (2 - amino-acetyl) -4 - (5 - phenyl-1H-imidazol-2 - yl ) pyrrolidine-2 - carboxylic acid and 1 - (2 - amino-acetyl) -4 - (4 - phenyl-1H-imidazol-2 - yl) pyrrolidine-2 - carboxylic acid.
In some embodiments, E is C (O) OR 6Example comprises the compound as giving a definition: wherein E is C (O) OH.In other embodiments, E is C (O) NR 6R 7In some compounds, E is C (O) NH 2In other compound, E is C (O) NR 6R 7, R 6Be H, and R 7Be selected from optional substituted C 1-10Alkyl, optional substituted C 3-20Naphthenic base, optional substituted C 6-20Aryl, optional substituted 3-20 unit's Heterocyclylalkyl and the first heteroaryl of optional substituted 5-20.
In other embodiments; E is the carboxylic acid bioisostere; As; For instance; Imidazoles,
Figure BDA0000152435510000225
azoles, thiazole, pyrazoles, triazole,
Figure BDA0000152435510000226
diazole, thiadiazoles or tetrazolium, it can be chosen wantonly separately and be substituted.The exemplary compounds of these embodiments includes, but is not limited to N-[1-(2-glycyl)-5-(1H-tetrazolium-5-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(1H-imidazoles-2-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(5-methyl isophthalic acid H-imidazoles-2-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(5-sec.-propyl-1H-imidazoles-2-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(
Figure BDA0000152435510000231
azoles-2-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(5-sec.-propyl
Figure BDA0000152435510000232
azoles-2-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(5-methyl
Figure BDA0000152435510000233
azoles-2-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(4-methyl azoles-2-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(1H-pyrazoles-5-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(3-sec.-propyl-1H-pyrazoles-5-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(3-methyl isophthalic acid H-pyrazoles-5-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(1H-1; 2; 4-triazole-5-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(3-methyl isophthalic acid H-1; 2; 4-triazole-5-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(3-sec.-propyl-1H-1; 2; 4-triazole-5-yl) tetramethyleneimine-3-yl] BM, N-[1-(2-glycyl)-5-(1; 3; 4-
Figure BDA0000152435510000235
diazole-2-yl) tetramethyleneimine-3-yl] BM and N-[1-(2-glycyl)-5-(5-methyl isophthalic acid; 3,4- diazole-2-yl) tetramethyleneimine-3-yl] BM.
In some embodiments, when A be (CH 2) k-Y ', Y ' are NH 2, k is 0, and E is C (O) OH, and B is NHC (O), and Z is when being phenyl, then R 1It or not methyl.In other embodiments, when A be (CH 2) k-Y ', Y ' are NH 2, k is 0, R 1Be methyl, E is C (O) OH, and Z ' is when being phenyl, and then phenyl is replaced by at least one Q base.In other other embodiment, when A is (CH 2) k-Y ', Y ' are NH 2, k is 0, R 1Be methyl, B is NHC (O), and Z is when being phenyl, and then E is not C (O) OH.In other embodiments, when A be (CH 2) k-Y ', Y ' are NH 2, R 1Be methyl, E is C (O) OH, and B is NHC (O), and Z ' is when being phenyl, and then k is 1 or 2.In another other embodiment, when A is (CH 2) k-Y ', k are 0, R 1Be methyl, E is C (O) OH, and B is NHC (O), and Z ' is when being phenyl, and then Y ' is not NH 2
Compound according to the present invention comprises having following structure person and pharmacy acceptable salt, ester, hydrate and prodrug:
Figure BDA0000152435510000241
On the other hand, the present invention provides compound and pharmacy acceptable salt, ester, hydrate and the prodrug with formula III:
Figure BDA0000152435510000242
Wherein:
Y ' is OR 2Or NR 2R 3
K is 0,1 or 2;
Z ' is selected from H, (CH 2) m-C 6-20Aryl, (CH 2) m-5-20 unit heteroaryl, C (O) (CH 2) m-C 6-20Aryl, C (O) (CH 2) m-5-20 unit heteroaryl, (CH 2) mC (O)-C 6-20Aryl, (CH 2) mC (O)-5-20 unit heteroaryl, S (O) 2(CH 2) m-C 6-20Aryl and S (O) 2(CH 2) m-5-20 unit heteroaryl, wherein C 6-20Aryl and 5-20 unit heteroaryl can be chosen wantonly separately by 1-5 Q base and replace;
M is 0,1 or 2;
The each appearance of Q all is independently selected from optional substituted C 1-10Alkyl, optional substituted C 2-10Thiazolinyl, optional substituted C 2-10Alkynyl, optional substituted C 3-20Naphthenic base, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl, the first Heterocyclylalkyl of optional substituted 3-20, the first heteroaryl of optional substituted 5-20, F, Cl, Br, I, CN, CF 3, OCF 3, NO 2, OR 8, SR 8, S +R 8 2, S (O) R 8, S (O) 2R 8, S (O) 2OH, S (O) 2NR 8R 9, NR 8S (O) 2R 9, C (O) R 8, C (O) OR 8, C (O) NR 8R 9, OC (O) R 8, NR 8R 9, NR 8C (O) R 9, NR 8C (O) OR 9, NR 8C (O) NR 8R 9And N +R 8 3
R 1Be selected from H, optional substituted C 1-10Alkyl, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl and amino acid side chain;
R 2And R 3Be selected from H, optional substituted C independently of one another 1-10Alkyl, optional substituted C 3-20Naphthenic base, optional substituted C 7-20Aralkyl, optional substituted C 6-20Aryl, the first Heterocyclylalkyl of optional substituted 3-20, the first heteroaryl of optional substituted 5-20, C (O) R 6, C (O) OR 6, C (O) NR 6R 7, S (O) 2R 6And S (O) 2NR 6R 7
Perhaps, R 2And R 3Form 3-20 unit heterocycle with their institute's bonded nitrogen-atoms, said heterocycle randomly contains 1-4 ring hetero atom (this ring hetero atom is independently selected from O, N and S) and chooses wantonly by 1-5 Q base and replaces;
R 4Be OR 6Or NR 6R 7
R 5Be H or optional substituted C 1-10Alkyl;
R 6And R 7Be selected from H, optional substituted C independently of one another 1-10Alkyl, optional substituted C 3-20Naphthenic base, optional substituted C 2-10Thiazolinyl, optional substituted C 2-10Alkynyl, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl, the first Heterocyclylalkyl of optional substituted 3-20, the first heteroaryl of optional substituted 5-20, C (O) R 8, C (O) OR 8And C (O) NR 8R 9
Perhaps, R 6And R 7Form 3-20 unit heterocycle with their institute's bonded nitrogen-atoms, said heterocycle randomly contains 1-4 ring hetero atom (this ring hetero atom is independently selected from O, N or S) and is randomly replaced by 1-5 Q base; And
R 8And R 9Be selected from H, optional substituted C independently of one another 1-10Alkyl, optional substituted C 3-20Naphthenic base, optional substituted C 2-10Thiazolinyl, optional substituted C 2-10Alkynyl, optional substituted C 6-20Aryl, optional substituted C 7-20Aralkyl, optional substituted 3-20 unit's Heterocyclylalkyl and the first heteroaryl of optional substituted 5-20;
Condition is that said compound is not 1-(the amino propionyl group of 2-)-4-benzamido-tetramethyleneimine-2-formic acid.
In some embodiments, k is 0, and in other embodiments, k is 1.
In some embodiments, Y ' is NR 2R 3And R 2For H (is that Y ' is NHR 3) and R 3Being selected from H (is that Y ' is NH 2), optional substituted C 1-10Alkyl, C (O) R 6Or C (O) OR 6In some embodiments, Y ' is NR 2R 3, R 2Be H, R 3Be C (O) R 6And R 6For H (is R 3Be C (O) H) or optional substituted C 1-10Alkyl (R for example 3Be C (O) CH 3).In other embodiments, Y ' is NR 2R 3And R 2And R 3Be optional substituted C independently of one another 1-10Alkyl.In other other embodiment, Y ' is OR 2And R 2Be H (being that Y is OH) or optional substituted C 1-10Alkyl.
In certain embodiments, R 1Be H.In other embodiments, R 1For amino acid side chain and said amino acid are selected from Xie Ansuan, leucine, Isoleucine, methionine(Met), L-Ala, phenylalanine(Phe), tyrosine, tryptophane, Serine, Threonine, halfcystine, Methionin, l-arginine, Histidine, aspartic acid, L-glutamic acid, l-asparagine and Stimulina, condition is that compound is not 1-(the amino propionyl group of 2-)-4-benzamido-tetramethyleneimine-2-formic acid.
Other embodiment of the present invention comprises the compound as giving a definition: R wherein 4Be OR 6(for example OH).Perhaps, R 4Can be NR 6R 7, R wherein 6Be H and R 7Being selected from H (also is R 4Be NH 2), optional substituted C 1-10Alkyl, optional substituted C 3-20Naphthenic base, optional substituted C 6-20Aryl, optional substituted 3-20 unit's Heterocyclylalkyl or the first heteroaryl of optional substituted 5-20.In other other alternate embodiment, R 6And R 7Form 3-20 unit heterocycle with their institute's bonded nitrogen-atoms, said heterocycle be selected from piperidines, piperazine, morpholine, thiomorpholine, tetramethyleneimine,
Figure BDA0000152435510000261
Azoles alkane, thiazolidine and imidazolidine, it can be chosen wantonly separately by 1-5 Q base and replace.
In some embodiments, Z ' is for choosing wantonly by 1-5 Q base substituted C (the O) (CH of institute 2) m-C 6-20Aryl, and m to be 0 (be that Z is optional by basic substituted C (the O)-C of 1-5 Q 6-20Aryl).The exemplary compounds of these embodiments comprises the compound as giving a definition: wherein Z ' is a benzoyl-.In other example, Z is by 1-5 the substituted benzoyl-of Q base, as, for instance, F, Cl, Br, I, C 1-10Alkyl, CF 3, OCF 3, NO 2, O-C 1-10Alkyl, OH, NH 2, NH (C 1-10Alkyl), N (C 1-10Alkyl) 2And NHC (O) C 1-10Alkyl.
In some embodiments, working as Y ' is NH 2, k is 0, R 4Be OH, R 5Be H, and Z ' is when being benzoyl-, then R 1It or not methyl.In other embodiments, working as Y ' is NH 2, k is 0, R 1Be methyl, R 4Be OH, R 5Be H, and Z ' is when being benzoyl-, then said benzoyl-is replaced by at least one Q base.In other other embodiment, working as Y ' is NH 2, k is 0, R 1Be methyl, R 5Be H, and Z is when being benzoyl-, then R 4Not OH.In other embodiments, working as Y ' is NH 2, R 1Be methyl, R 4Be OH, R 5Be H, and Z ' is when being benzoyl-, then k is 1 or 2.In other other embodiment, when k is 0, R 1Be methyl, R 4Be OH, R 5Be H, and Z ' is when being benzoyl-, then Y ' is not NH 2
Compound according to the present invention comprises compound and pharmacy acceptable salt, ester, hydrate and the prodrug with following structure:
The example of the suitable prodrug of any compound of the present invention includes, but is not limited to
Figure BDA0000152435510000272
oxazolidone or imidazolidone prodrug.
On the other hand, the present invention provides pharmaceutical composition, and it comprises according to compound of the present invention and pharmaceutically acceptable carrier.
Again on the other hand, the present invention provides the method for prevention or treatment pathological condition, it comprise with the treatment significant quantity according to compound of the present invention or host (like the mankind) administration of pharmaceutical composition to needs are arranged.Can use the example of the pathological condition of compounds for treating of the present invention or prevention to include, but is not limited to cardiovascular disorder (for example auricular fibrillation, auricular flutter, ventricular tachycardia or ventricular fibrillation); Osteoporosis; The airway epithelial inflammation; Honeycomb weave (alveolar tissue) illness; Bladder incontinence; Hearing loss, for example since the cochlea disease cause; The endothelium pathology; Mellitus comprise diabetic retinopathy and diabetic neuropathy; The disease relevant with CNS; Local asphyxia (the for example local asphyxia of cns, spinal cord, brain or brain stem); The dental tissue illness comprises periodontopathy; Kidney disease; Hematology performance (for example anaemia, leukopenia, thrombocytopenia and pancytopenia) is especially after utilizing cell growth-inhibiting compounds for treating or radiotherapy; Wound (for example the appearance wound and since wound cause go deep into wound etc.); Erection problem; The urine bladder incontinence; Neuropathic pain; Inferior chronic and chronic inflammatory diseases; Cancer; Marrow and stem cell move and grow failure; During cell and tissue transplantation or the patient's condition that takes place in medical journey operating period (for example operation); The patient's condition that is caused because of excess reactivity oxygen, radical or nitrogen protoxide; Conceived disease or illness (for example preeclampsia and premature labor); And apoplexy.
Can be according to compound of the present invention and pharmaceutical composition through preparation for through parenteral or oral administration.
A. definition
Except as otherwise noted, following definitions is that the buzzword that is used in the hereinafter description provides.
In entire description and claims, used three-letter code of natural amino acid, also used three-letter code of common acceptable other a-amino acid, for example sarkosine (Sar).When L or D form do not specialize, will be appreciated that said amino acid can be L or D form.The mixture of the D of equimolar amount and L compound is named as racemic modification and utilizes prefix DL to indicate, for example the DL-leucine.Perhaps, prefix rac-capable of using indicates (for example rac-leucine) or utilizes prefix [+/-] to indicate.The present invention includes the compound of formula I, II and III, and all possible steric isomer of the specific compound pointed out of this paper.
Term among this paper " peptide " refers to by two of peptide bond banded or more a plurality of molecular chain.Peptide can contain one or more naturally occurring amino acid, one or more alpha-non-natural amino acid, one or more non-amino acid but can form molecule or its mixture of peptide bond.
Term " amino acid " refers to have the molecule of general formula NHR-CHR '-COOH, and (wherein R is that H and R ' are amino acid side chain; Or R and R ' form ring with its bonded carbon and nitrogen; Proline(Pro) for example), it can form peptide bonds with one or more other molecules with same general formula.Said term comprises L and D two seed amino acids.
" naturally occurring amino acid " refers to a kind of in following 20 seed amino acids: Ala (A), Cys (C), Ser (S), Thr (T), Asp (D), Glu (E), Asn (N), Gln (Q), His (H), Arg (R), Lys (K), Ile (I), Leu (L), Met (M), Val (V), Phe (F), Tyr (Y), Trp (W), Gly (G), and Pro (P).Generally speaking, these are L-amino acid, but the present invention also allows to use D-amino acid.
The term " lysine-mimetic " that here uses refers to alpha-non-natural amino acid, and it comprises C 5-6Aliphatics or aromatic ring and at least two basic amine functional groups (that is, except that the N-terminal amine, also having at least one basic amine functional group).In some cases; Lysine-mimetic has formula NHR-CHR '-COOH; Wherein R and R ' form 5-6 unit ring with its bonded carbon and nitrogen, and wherein this ring (a) contains at least one extra theheterocyclic nitrogen atom, for example imidazolidine-2-formic acid (Ica); Or (b) have amine substituting group, for example amino-tetramethyleneimine-2-formic acid (4Amp) or amino-piperadine-2-formic acid (4Ampi).In other cases, lysine-mimetic has formula NHR-CHR '-COOH, and wherein R is that H and R ' are for containing C 5-6The side chain of aliphatics or aromatic ring, wherein (a) ring contains at least one theheterocyclic nitrogen atom or has an amine substituting group, and (b) ring is separated by 1 or 2 atom and amino acid backbone methylene radical.The non-limitative example of this lysine-mimetic is amino-phenylalanine(Phe) (4AmF), and wherein 1 atom is separated ring and main chain.Lysine-mimetic also can have formula NHR-CR ' R "-COOH, wherein R is H and R ' and R " form C together 5-6Aliphatics or aromatic ring, wherein ring contains at least one theheterocyclic nitrogen atom or has an amine substituting group.A non-limitative example of this type lysine-mimetic is 4-amino-piperadine-4-formic acid (Pip).The definition of " lysine-mimetic " also comprises non-natural β-and gamma-amino acid, and it comprises C 5-6Aliphatics or aromatic ring, and as at least two above-mentioned basic amine functional groups, for example 3,5-diamino--phenylformic acid (Damba).Other lysine-mimetic is a 4-aminoproline analogue, and wherein there is not (for example 3-Aminocyclopentane formic acid) in the nitrogen on the proline(Pro) ring or is positioned at another position (for example 3-amino-pyrrolidine-1-formic acid or 3-amino-pyrrolidine-1-methane amide) of proline(Pro) ring.In any lysine-mimetic, basic amine functional group can be primary amino (for example 4AmF, Damba, 4Ampi and 4Amp) or secondary amino group (for example Pip and Ica).Example with lysine-mimetic of aliphatics cyclammonium group and arylamines comprises Damba, 4Amp, 4Ampi, Ica, Pip and 4AmF, and it has following structures:
Term " halogen " refers to F, Cl, Br and I.
The term " alkyl " that here uses but exist singly or as the part of another group refer to be substituted or unsubstituted aliphatics hydrocarbon chain (for example having 1 to 10 carbon atom), it can be straight or branched.The example of alkyl comprises methyl (Me), ethyl (Et), propyl group (for example n-propyl and sec.-propyl), butyl (for example normal-butyl, isobutyl-, sec.-butyl, the tertiary butyl), amyl group similar groups such as (n-pentyl, isopentyl, neo-pentyls).In the definition of " alkyl ", especially comprise optional substituted aliphatic hydrocarbon chain.
The term " thiazolinyl " that here uses but exist singly or as the part of another group refer to be substituted or unsubstituted aliphatics hydrocarbon chain (for example having 2 to 10 carbon atoms), it can be straight or branched and contains one or more carbon-to-carbon double bonds.Said one or more pairs of keys can be inside (for example in 2-butylene) or terminal (for example in 1-butylene).Preferably, alkenyl part contains one or two pair key.Term " thiazolinyl " comprises E and the Z isomer that each has one or more pairs of keys.In the definition of " thiazolinyl ", especially comprise optional substituted aliphatic hydrocarbon chain.The example of alkenyl part comprises vinyl, allyl group and crotonyl (for example 1-butylene and 2-butylene).
Term used herein " alkynyl " but exist singly or as the part of another group refer to be substituted or unsubstituted aliphatics hydrocarbon chain (for example having 2 to 10 carbon atoms), it can be straight or branched and contains one or more carbon-to-carbon three keys.Said one or more three key can be inside (for example in 2-butyne) or terminal (for example in ethyl acetylene).In the definition of " alkynyl ", especially comprise optional substituted aliphatic hydrocarbon chain.The example of alkynyl comprises similar groups such as ethynyl, proyl, butynyl, pentynyl.
As use here; But exist singly or as the part of another group; Term " naphthenic base " refers to be substituted or unsubstituted non-aromatic carbocylic radical (for example having 3 to 20 ring carbon atoms) and optional contains one or more (for example 1,2 or 3) two keys or three key, comprises cyclisation alkyl, thiazolinyl and alkynyl.Naphthenic base can be monocycle (for example cyclohexyl) or many rings (for example fused rings, bridge joint ring or volution system), and wherein carbon atom is positioned at the inside or the outside of member ring systems.But any suitable ring position covalent bonding of cycloalkyl moiety to defined chemical structure.The example of naphthenic base comprises cyclopropyl, cyclopropyl methyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl methyl, cyclohexyl ethyl, suberyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatriene base, norcamphyl, falls similar groups such as pinane base (norpinyl), norcaryl (norcarnyl), adamantyl (adamantly), spiral shell [4.5] decyl, homologue, isomer.In the definition of naphthenic base, also comprise and have the part that one or more and cycloalkyl ring condense the aromatic ring of (promptly having the common key), the for example benzo derivative of pentamethylene (indanyl), cyclohexyl benzo derivative (tetralyl) etc.In the definition of " naphthenic base ", especially comprise optional substituted carbocyclic ring.
The term " aryl " that here uses but exist singly or as the part of another group refer to be substituted or unsubstituted aromatic series monocycle or polynuclear hydrocarbon, for example, for instance, phenyl, naphthyl, anthryl, phenanthryl etc.In some embodiments, aryl has 6 to about 20 carbon atoms.Any suitable ring position of aryl moiety can covalently be connected to defined chemical structure (for example 1-naphthyl, 2-naphthyl etc.).In the definition of " aryl ", especially comprise optional substituted aromatic hydrocarbons.
Term " aralkyl " refers to defined aryl moiety here, itself and the moieties Cheng Jian that here defines.Aralkyl covalently is connected to defined chemical structure through its alkyl.Aralkyl can be chosen wantonly on aryl moiety, moieties or two portions and be substituted.
As use here; But exist singly or as the part of another group; " Heterocyclylalkyl " refers to be substituted or unsubstituted non-aromatic naphthenic base (for example having 3 to 20 annular atomses); It contains the heteroatoms that 1-4 is independently selected from oxygen (O), nitrogen (N) and sulphur (S), and randomly contains one or more (for example 1,2 or 3) two keys or three key.Heterocyclylalkyl can be connected to defined chemical structure at the heteroatoms or the carbon atom place of any generation rock steady structure.One or more N in heterocycloalkyl ring or S atom can be oxidized (for example N-hydroxy piperidine, morpholine N-oxide compound, thiomorpholine S-oxide compound, thiomorpholine S, S-dioxide).The example of Heterocyclylalkyl comprises morpholine, thiomorpholine, pyrans, imidazolidine, tetrahydroglyoxaline,
Figure BDA0000152435510000321
azoles alkane, pyrazolidine, pyrazoline, tetramethyleneimine, pyrroline, THF, THTP, piperidines, piperazine etc.In the definition of Heterocyclylalkyl, also comprise having and one or morely condense the part of the aromatic ring of (promptly having the common key), for example benzimidazoline, chroman, chromene, indoline tetrahydroquinoline etc. with the ring heterocycloalkyl ring.Heterocyclylalkyl also can contain one or more oxo bases; For example phthalimide, piperidone,
Figure BDA0000152435510000322
oxazolidone, pyrimidine-2; 4 (1H, 3H)-diketone, pyridine-2 (1H)-ketone etc.In the definition of " Heterocyclylalkyl ", especially be included in optional substituted member ring systems on the arbitrary heteroatoms that produces rock steady structure and/or the carbon atom.
As use, but exist singly or as the part of another group, " heteroaryl " refers to monocycle or Ppolynuclear aromatic member ring systems, it has 5 to 20 annular atomses and contains 1-4 and is independently selected from the heteroatoms of O, N and S. hereNormally, heteroaryl ring does not contain O-O, S-S or S-O key.Heteroaryl comprises and benzyl ring condensed bicyclic heteroaryl ring.Heteroaryl can be connected to defined chemical structure at the heteroatoms or the carbon atom place of any generation rock steady structure.One or more N in heteroaryl ring or S atom can be oxidized (for example N-pyridone, pyridine N-oxides, thiophene S-oxide compound, thiophene S, S-dioxide).The example of heteroaryl comprises for example pyrroles, furans, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazoles, imidazoles, isothiazole, thiazole, thiadiazoles, different
Figure BDA0000152435510000323
azoles, azoles,
Figure BDA0000152435510000325
diazole, indoles, isoindole, cumarone, thionaphthene, quinoline, 2-toluquinoline, isoquinoline 99.9, quinoxaline, quinazoline, benzotriazole, benzo tetrazolium, indazole, benzoglyoxaline, benzothiazole, benzisothiazole, benzisoxa
Figure BDA0000152435510000326
azoles, benzo
Figure BDA0000152435510000327
diazole, benzo
Figure BDA0000152435510000328
azoles, cinnolines, 1H-indazole, 2H-indazole, pyrrocoline, isobenzofuran, naphthyridine (naphyridine), phthalazines, pteridine, purine,
Figure BDA0000152435510000329
azoles and pyridine, thiazole and pyridine, imidazopyridine, furo pyridine (furopyridine), thienopyridine, Pyridopyrimidine, pyrido-pyrazine, pyrido pyridazine, thieno-thiazole, thieno-
Figure BDA00001524355100003210
azoles and Thienoimidazole.In the definition of " heteroaryl ", especially be included in optional substituted aromatic nucleus system on the arbitrary heteroatoms that produces rock steady structure and/or the carbon atom.
Term " heterocyclic radical " refers to the heteroaryl or the Heterocyclylalkyl of place like this definition.
As use, " carboxylic acid bioisostere " refers to have with the similar chemistry of carboxylic moiety or physical properties and produces substituting group or the group with the similar biological nature of carboxylic moiety widely. hereUsually referring to R.B.Silverman, The Organic Chemistry of Drug Design and Drug Action (Academic Press, 1992).The example of carboxylic acid bioisostere include, but is not limited to acid amides, sulphonamide, sulfonic acid, phosphonamidic acid (phosphonamidic acid), alkyl phosphonates, N-malonamide nitrile, 3-hydroxyl-4H-pyrans-4-ketone, imidazoles,
Figure BDA0000152435510000331
Azoles, thiazole, pyrazoles, triazole,
Figure BDA0000152435510000332
Diazole, thiadiazoles or tetrazolium, it can be chosen wantonly separately and be substituted (for example by C 1-10Alkyl, OH etc. replace).
As use, " acid amides bioisostere " refers to have with the similar chemistry of amide moieties or physical properties and produces substituting group or the group with the similar biological nature of amide moieties widely. hereUsually referring to R.B.Silverman, The Organic Chemistry of Drug Design and Drug Action (Academic Press, 1992).The example of acid amides bioisostere include, but is not limited to carboxylic acid, sulphonamide, sulfonic acid, phosphonamidic acid, alkyl phosphonates, N-malonamide nitrile, 3-hydroxyl-4H-pyrans-4-ketone, imidazoles,
Figure BDA0000152435510000333
Azoles, thiazole, pyrazoles, triazole, Diazole, thiadiazoles or tetrazolium, it can be chosen wantonly separately and be substituted (for example by C 1-10Alkyl, OH etc. replace).
Term " hydrophobic group " refers to optional substituted aromatic carbon ring, the first aromatic carbon ring of preferred 6-to 12-.Hydrophobic group can be like optional being substituted of hereinafter being discussed.Exemplary hydrophobic group comprises phenmethyl, phenyl and naphthyl.
As use, term " optional being substituted " refers to that one or more Wasserstoffatomss (for example 1,2,3,4,5 or 6 Wasserstoffatoms) of group can be replaced into respectively and generally is used for pharmaceutical chemical replacement atom or substituting group. hereEach substituting group can be identical or different.Suitable substituent example includes, but is not limited to alkyl, thiazolinyl, alkynyl, naphthenic base, aryl, aralkyl, Heterocyclylalkyl, heteroaryl, OR 6(for example hydroxyl, alkoxyl group (for example methoxyl group, oxyethyl group and propoxy-), aryloxy, heteroaryloxy, aralkoxy, ether, ester, carbamate etc.), hydroxyalkyl, alkoxy carbonyl, alkoxyl group alkoxyl group, perhaloalkyl radical, perfluoroalkyl (CF for example 3, CF 2CF 3), perfluoro alkoxy (OCF for example 3, OCF 2CF 3), alkoxyalkyl, SR 6(for example thiol, alkylthio, arylthio, heteroarylthio, aromatic alkylthio), S +R 6 2, S (O) R 6, SO 2R 6, NR 6R 7(for example primary amine (is NH 2), secondary amine, tertiary amine, acid amides, carbamate, urea etc.), hydrazides, halogenide, nitrile, nitro, sulfide, sulfoxide, sulfone, sulphonamide, thiol, carboxyl, aldehyde, ketone, carboxylic acid, ester, acid amides, imines and imide; Comprise its seleno and thio group verivate, wherein each substituting group can be chosen wantonly by further replacement.Preferably, can have 1-3 optional substituting group, wherein substituting group is like the Q base of definition here.In the substituted embodiment of the functional group with aromatic carbon ring, this substituted number is generally less than about 10 replacements, and is preferred, is about 1 to 5 replacement, preferably about 1 or 2 replacement.
The carbon number that uses in the definition herein (C for example 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 6-20Aryl etc.) refer to carbon backbone chain and carbon side chain, but do not comprise substituent carbon atom.
At this specification sheets different positions, the substituting group of compound of the present invention is open with the mode of group or scope.The present invention especially is intended to comprise each independent Asia combination of the member of said group and scope.For example, term " C 1-6Alkyl " especially be intended to individually openly C 1, C 2, C 3, C 4, C 5, C 6, C 1-C 6, C 1-C 5, C 1-C 4, C 1-C 3, C 1-C 2, C 2-C 6, C 2-C 5, C 2-C 4, C 2-C 3, C 3-C 6, C 3-C 5, C 3-C 4, C 4-C 6, C 4-C 5And C 5-C 6Alkyl.Similarly, term " C 1-10Alkyl " especially be intended to individually openly C 1, C 2, C 3, C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 1-C 10, C 1-C 9, C 1-C 8, C 1-C 7, C 1-C 6, C 1-C 5, C 1-C 4, C 1-C 3, C 1-C 2, C 2-C 10, C 2-C 9, C 2-C 8, C 2-C 7, C 2-C 6, C 2-C 5, C 2-C 4, C 2-C 3, C 3-C 10, C 3-C 9, C 3-C 8, C 3-C 7, C 3-C 6, C 3-C 5, C 3-C 4, C 4-C 10, C 4-C 9, C 4-C 8, C 4-C 7, C 4-C 6, C 4-C 5, C 5-C 10, C 5-C 9, C 5-C 8, C 5-C 7, C 5-C 6, C 6-C 10, C 6-C 9, C 6-C 8, C 6-C 7, C 7-C 10, C 7-C 9, C 7-C 8, C 8-C 10, C 8-C 9And C 9-C 10Alkyl.
Compound of the present invention can contain asymmetric atom (being also referred to as chiral centre), and some compounds can contain one or more asymmetric atoms or center, and therefore it can produce optical isomer (enantiomer) and diastereomer.The present invention includes these enantiomers and diastereomer, and R racemic modification and fractionation, enantiomer-pure and S steric isomer, and other mixture of R and S steric isomer, and pharmacy acceptable salt.The optical isomer of pure form can obtain in known by one of skill in the art standard method, and it is synthetic that it includes but not limited to form diastereoisomerism salt, kinetic resolution and asymmetry.The present invention also comprises the cis and the trans-isomer(ide) of the compound (for example alkene class and imines) that contains alkenyl part.Also will be appreciated that, the present invention includes all possible regional isomer and composition thereof, its pure form can known by one of skill in the art standard isolation methods obtain, and includes but not limited to column chromatography, tlc and HPLC.
Term " cell communication regulator ", " gap connect promotor ", " promoting the compound of gap junction communication " reach " gap connects the unlatching agent " etc.; All refer to promote, keep, the compound of normalizing gap connectivity cell-cell communication (GJIC), regardless of this effect specific mechanism behind.More particularly, term " gap the connects the unlatching agent " normalizing of making a comment or criticism (i.e. increase) can be passed through the molecule that the spatial gap connects in extracellular and the cell and exchange, and/or the material of ability normalizing or increase GJIC.
Term " agonist " refer to can with tissue, cell or the interactional compound of cell part, this tissue, cell or cell partly are the target spot of AAP, AAP10 or HP5 compound (or its functional analogue)) so that in this tissue, cell or cell part, cause and AAP, AAP10 or the essentially identical physiological response of HP5 compound (or its functional analogue).On the one hand, this physiological response for shrink, one or more in lax, the secretion, enzyme activation etc.Preferably, this compound partly combines with this tissue, cell or cell.On the one hand, the receptors bind on compound and this tissue, cell or the cell part, this receptor combines with AAP, AAP10 or HP5 compound (or its functional analogue).
Term " antagonist " refers in tissue, cell or cell part with after AAP, AAP10 or HP5 compound (or its functional analogue) contacts, suppress or antagonism this tissue, cell or cell partly in the compound of observed one or more physiological responses.On the one hand, this physiological response for shrink, one or more in lax, the secretion, enzyme activation etc.Preferably, said compound partly combines with this tissue, cell or cell.On the one hand; Said compound and this tissue, cell or cell are partly gone up and AAP, AAP10 or HP5 compound (or its functional analogue) bonded receptors bind, and/or suppress the combining of one or more and this receptor in AAP, AAP10 or the HP5 compound (or its functional analogue).
As use, " normalizing " refers to the change on the physiological response, does not have significantly different to cause this reaction to become with observed reaction in normal patient. hereTherefore, according to related pathology, normalizing possibly relate to the increase or the reduction of reaction.
B. exemplary compounds
Exemplary compounds according to the present invention is listed below.In some cases, compound selects for use in the bracket after name is contained in chemical name.
Compound 1: (2S, 4R) 1-(2-amino-ethanoyl)-4-(4-nitro-benzoyl-amido)-tetramethyleneimine-2-formic acid (H-Gly-(and 2S, 4R)-4Amp (4-nitro benzoyl)-OH);
Compound 2: (2S, 4R) 1-(2-amino-ethanoyl)-4-benzoyl-amido-tetramethyleneimine-2-formic acid ((2S, 4R)-1-(2-glycyl)-4-benzamido-tetramethyleneimine-2-formic acid (H-Gly-(2S, 4R)-4Amp (benzoyl-)-OH);
Compound 3: (2S, 4R) 1-(2-amino-ethanoyl)-4-(4-methyl-benzoyl-amido)-tetramethyleneimine-2-formic acid (H-Gly-(and 2S, 4R)-4Amp (4-methyl benzoyl)-OH);
Compound 4: (2S, 4R) 1-(2-amino-ethanoyl)-4-(4-methoxyl group-benzoyl-amido)-tetramethyleneimine-2-formic acid (H-Gly-(and 2S, 4R)-4Amp (4-anisoyl)-OH);
Compound 5: (2S, 4R) 1-(3-amino-propionyl group)-4-benzoyl-amido-tetramethyleneimine-2-formic acid (H-Ala-(and 2S, 4R)-4Amp (benzoyl-)-OH);
Compound 6: (2S, 4R) 1-(2-amino-4-carboxyl-butyryl radicals)-4-benzoyl-amido-tetramethyleneimine-2-formic acid (H-Glu-(and 2S, 4R)-4Amp (benzoyl-)-OH);
Compound 7: (2S, 4R) 1-[2-amino-3-(1H-indol-3-yl)-propionyl group]-4-benzoyl-amido-tetramethyleneimine-2-formic acid (H-Trp-(and 2S, 4R)-4Amp (benzoyl-)-OH);
Compound 8: (2S, 4R) 1-(2-amino-4-methyl-pentanoyl)-4-benzoyl-amido-tetramethyleneimine-2-formic acid (H-Leu-(and 2S, 4R)-4Amp (benzoyl-)-OH);
Compound 9: (2S, 4R) 1-(2-amino-3-phenyl-propionyl group)-4-benzoyl-amido-tetramethyleneimine-2-formic acid (H-Phe-(and 2S, 4R)-4Amp (benzoyl-)-OH);
Compound 10: (2S, 4R) 1-(2-amino-ethanoyl)-4-(4-hydroxyl-benzoyl-amido)-tetramethyleneimine-2-formic acid (H-Gly-(and 2S, 4R)-4Amp (4-hydroxy benzoyl)-OH);
Compound 11: (2S, 4S) 1-(2-amino-ethanoyl)-4-(4-methoxyl group-benzoyl-amido)-tetramethyleneimine-2-formic acid (H-Gly-(and 2S, 4S)-4Amp (4-anisoyl)-OH);
Compound 12: (2S, 4S) 1-(2-amino-ethanoyl)-4-(4-methyl-benzoyl-amido)-tetramethyleneimine-2-formic acid (H-Gly-(and 2S, 4S)-4Amp (4-methyl benzoyl)-OH);
Compound 13: (2S, 4S) 1-(2-amino-ethanoyl)-4-(4-nitro-benzoyl-amido)-tetramethyleneimine-2-formic acid (H-Gly-(and 2S, 4S)-4Amp (4-nitro benzoyl)-OH);
Compound 14: (2S, 4S) 1-(2-amino-ethanoyl)-4-benzoyl-amido-tetramethyleneimine-2-formic acid (H-Gly-(and 2S, 4S)-4Amp (benzoyl-)-OH);
Compound 15: (2S, 4S) 1-(2-amino-4-carboxyl-butyryl radicals)-4-benzoyl-amido-piperidines-2-formic acid (H-Glu-(and 2S, 4S)-4Ampi (benzoyl-)-OH);
Compound 16: (2S, 4S) 1-(2-amino-4-methyl-pentanoyl)-4-benzoyl-amido-piperidines-2-formic acid (H-Leu-(and 2S, 4S)-4Ampi (benzoyl-)-OH);
Compound 17: (2S, 4S) 4-benzoyl-amido-1-(2,6-diamino--caproyl)-piperidines-2-formic acid (H-Lys-(and 2S, 4S)-4Ampi (benzoyl-)-OH);
Compound 18: (2S, 4S) 1-(2-amino-ethanoyl)-4-benzoyl-amido-piperidines-2-formic acid (H-Gly-(and 2S, 4S)-4Ampi (benzoyl-)-OH);
Compound 19: (2S, 4S) 1-(3-amino-propionyl group)-4-benzoyl-amido-piperidines-2-formic acid (H-Ala-(and 2S, 4S)-4Ampi (benzoyl-)-OH);
Compound 20: (2S, 4S) 1-[2-amino-3-(1H-indol-3-yl)-propionyl group]-4-benzoyl-amido-piperidines-2-formic acid (H-Trp-(and 2S, 4S)-4Ampi (benzoyl-)-OH);
Compound 21: (2S, 4S) 1-(2-amino-3-phenyl-propionyl group)-4-benzoyl-amido-piperidines-2-formic acid (H-Phe-(and 2S, 4S)-4Ampi (benzoyl-)-OH);
Compound 22:1-(2-amino-4-carboxyl-butyryl radicals)-3-benzoyl--imidazolidine-2-formic acid (H-Glu-Ica (benzoyl-)-OH);
Compound 23:4-(2-amino-acetylamino)-1-benzoyl-piperidine-4-formic acid (H-Gly-Pip (benzoyl-)-OH);
Compound 24:3-(2-amino-acetylamino)-5-(4-methyl-benzoyl-amido)-phenylformic acid (H-Gly-Damba (4-methyl benzoyl)-OH);
Compound 25:3-(2-amino-3-formamyl-propionyl group is amino)-5-benzoyl-amido-phenylformic acid (H-Asn-Damba (benzoyl-)-OH);
Compound 26:3-(2-amino-acetylamino)-5-benzoyl-amido-phenylformic acid (H-Gly-Damba (benzoyl-)-OH);
Compound 27: (2S, 4R) 3-[(4-benzoyl-amido-tetramethyleneimine-2-carbonyl)-amino]-propionic acid ((2S, 4R) H-4Amp (benzoyl-)-β-Ala-OH);
Compound 28: (2S, 4R) { [4-(4-nitro-benzoyl-amido)-tetramethyleneimine-2-carbonyl]-amino }-acetate ((2S, 4R) H-4Amp (4-nitro benzoyl)-Gly-OH);
Compound 29: (2S, 4R) { [4-(4-methoxyl group-benzoyl-amido)-tetramethyleneimine-2-carbonyl]-amino }-acetate ((2S, 4R) H-4Amp (4-anisoyl)-Gly-OH);
Compound 30: (2S, 4R) 2-{ [4-(4-methyl-benzoyl-amido)-tetramethyleneimine-2-carbonyl]-amino }-acetate ((2S, 4R) H-4Amp (toluyl)-Gly-OH);
Compound 31: (2S, 4R) 2-[(4-benzoyl-amido-tetramethyleneimine-2-carbonyl)-amino]-3-phenyl-propionic acid ((2S, 4R) H-4Amp (toluyl)-Phe-OH);
Compound 32: (2S, 4R) 2-[(4-benzoyl-amido-tetramethyleneimine-2-carbonyl)-amino]-4-methyl-valeric acid ((2S, 4R) H-4Amp (benzoyl-)-Leu-OH);
Compound 33: (2S, 4R) 4-benzoyl-amido-tetramethyleneimine-2-formic acid (5-amino-1-formyl radical-amyl group) acid amides ((2S, 4R) H-4Amp (benzoyl-)-Lys-OH);
Compound 34: (2S, 4R) 2-[(4-benzoyl-amido-tetramethyleneimine-2-carbonyl)-amino]-succinamic acid ((2S, 4R) H-4Amp (benzoyl-)-Asn-OH);
Compound 35: (2S, 4S) [(4-benzoyl-amido-tetramethyleneimine-2-carbonyl)-amino]-acetate ((2S, 4S) H-4Amp (benzoyl-)-Gly-OH);
Compound 36: (2S, 4S) [(4-(4-methoxyl group-benzoyl-amido)-tetramethyleneimine-2-carbonyl)-amino]-acetate ((2S4S) H-4Amp (4-anisoyl)-Gly-OH);
Compound 37: (2S, 4S) [(4-(4-nitro-benzoyl-amido)-tetramethyleneimine-2-carbonyl)-amino]-acetate ((2S, 4S) H-4Amp (4-nitro benzoyl)-Gly-OH);
Compound 38: (2S, 4S) [(4-(4-methyl-benzoyl-amido)-tetramethyleneimine-2-carbonyl)-amino]-acetate ((2S, 4S) H-4Amp (toluyl)-Gly-OH);
Compound 39: [2-amino-3-(4-benzoyl-amido-phenyl)-propionyl group is amino]-acetate (H-4AmF (benzoyl-)-Gly-OH);
Compound 40: [2-amino-3-(4-(4-methoxyl group-benzoyl-amido-phenyl)-propionyl group is amino]-acetate (H-4AmF (4-anisoyl)-Gly-OH);
Compound 41: [2-amino-3-(4-(4-nitro-benzoyl-amido-phenyl)-propionyl group is amino]-acetate (H-4AmF (4-nitro benzoyl)-Gly-OH);
Compound 42: [2-amino-3-(4-(4-methyl-benzoyl-amido-phenyl)-propionyl group is amino]-acetate (H-4AmF (toluyl)-Gly-OH);
Compound 43: [(1-benzoyl--imidazolidine-2-carbonyl)-amino] acetate (H-Ica (benzoyl-)-Gly-OH);
Compound 44:{ [1-(4-nitro-benzoyl-]-imidazolidine-2-carbonyl]-amino } acetate (H-Ica (4-nitro benzoyl)-Gly-OH);
Compound 45: (2S, 4S) { [4-benzoyl-amido-piperidines-2-carbonyl]-amino }-acetate ((2S4S) H-4Ampi (benzoyl-)-Gly-OH);
Compound 46: (2S, 4S) { [4-benzoyl-amido-piperidines-2-carbonyl]-amino }-propionic acid ((2S, 4S) H-4Ampi (benzoyl-)-β Ala-OH);
Compound 47: [(4-amino-1-benzoyl-piperidine-4-carbonyl)-amino]-acetate (H-Pip (benzoyl-)-Gly-OH);
Compound 48: (3-amino-5-benzoyl-amido-benzoyl-amido)-acetate (H-Damba (benzoyl-)-Gly-OH);
Compound 49: (3-amino-5-(4-methoxyl group-benzoyl-amido)-benzoyl-amido)-acetate (H-Damba (4-anisoyl)-Gly-OH);
Compound 50: (3-amino-5-(4-methyl-benzoyl-amido)-benzoyl-amido)-acetate (H-Damba (toluyl)-Gly-OH);
Compound 51: (3,5-diamino--benzoyl-amido)-acetate (H-Damba-Gly-OH);
Compound 52: (2S, 4R) 4-benzoyl-amido-1-(2-hydroxyl-ethanoyl)-tetramethyleneimine-2-formic acid (HAA-(2S, 4R) 4-Amp (benzoyl-)-OH);
Compound 53:4-benzoyl-amido-1-(2-hydroxyl-acetylamino)-naphthenic acid (HAA-Pip (benzoyl-)-OH);
Compound 54:3-benzoyl-amido-5-(2-hydroxyl-acetylamino)-phenylformic acid (HAA-Damba (benzoyl-)-OH);
Compound 55: (2S, 4S) 4-benzoyl-amido-1-(2-hydroxyl-ethanoyl)-piperidines-2-formic acid (HAA-(2S, 4S) 4-Ampi (benzoyl-)-OH);
Compound 56:1-benzoyl--3-(2-hydroxyl-ethanoyl)-imidazolidine-2-benzoic acid amides (HAA-Ica (benzoyl-)-NH 2);
Compound 57:1-benzoyl--3-(2-hydroxyl-ethanoyl)-imidazolidine-2-formic acid (HAA-Ica (benzoyl-)-OH);
Compound 58:3-(4-benzoyl-amido-phenyl)-2-(2-hydroxyl-acetylamino)-propionic acid (HAA-4AmF (benzoyl-)-OH);
Compound 59:N-{4-[2-formamyl-2-(2-hydroxyl-acetylamino)-ethyl]-phenyl }-BM (HAA-4AmF (benzoyl-)-NH 2);
Compound 60: (2S, 4R) 4-benzoyl-amido-1-(2-sulfydryl-ethanoyl)-tetramethyleneimine-2-formic acid (THAA-(and 2S, 4R)-4Amp (benzoyl-)-OH);
Compound 61: (2S, 4S) 4-benzoyl-amido-1-(2-sulfydryl-ethanoyl)-piperidines-2-formic acid (THAA-(and 2S, 4S)-4Ampi (benzoyl-)-OH);
Compound 62: (2S, 4S) 1-(2-amino-ethanoyl)-4-benzoyl-amido-piperidines-2-formic acid (H-Gly-(and 2S, 4S)-4Ampi (benzoyl-)-OH);
Compound 63: (2S, 4S) [(4-benzoyl-amido-piperidines-2-carbonyl)-amino]-acetate ((2S4S) H-4Ampi (benzoyl-)-Gly-OH);
Compound 64: (2S, 4R) 1-(2-glycyl)-4-benzamido-tetramethyleneimine-2-methane amide;
Compound 65: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-methylpyrrolidin-2-methane amide;
Compound 66: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-ethyl pyrrolidine-2-methane amide;
Compound 67: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-sec.-propyl tetramethyleneimine-2-methane amide;
Compound 68: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-cyclopropyl tetramethyleneimine-2-methane amide;
Compound 69: (2S, 4R) 4-benzamido--1-(2-(tert-butoxycarbonyl is amino) ethanoyl) tetramethyleneimine-2-methane amide;
Compound 70: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-(pentane-3-yl) tetramethyleneimine-2-methane amide;
Compound 71: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-cyclopentyl tetramethyleneimine-2-methane amide;
Compound 72: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-isobutyl-tetramethyleneimine-2-methane amide;
Compound 73: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-cyclobutyl tetramethyleneimine-2-methane amide;
Compound 74: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-tertiary butyl tetramethyleneimine-2-methane amide;
Compound 75: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-(tetrahydrochysene-2H-pyrans-4-yl) tetramethyleneimine-2-methane amide;
Compound 76: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-((R)-3-methylbutane-2-yl) tetramethyleneimine-2-methane amide;
Compound 77: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-((R)-3,3-dimethylbutane-2-yl) tetramethyleneimine-2-methane amide;
Compound 78: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-Phenylpyrrolidine-2-methane amide;
Compound 79: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-((R)-THF-3-yl) tetramethyleneimine-2-methane amide;
Compound 80: (2S, 4R) 1-(2-kharophen ethanoyl)-4-benzamido-tetramethyleneimine-2-formic acid;
Compound 81: (2S, 4R) 4-benzamido--1-(2-(methylamino) ethanoyl)-tetramethyleneimine-2-formic acid;
Compound 82: (2S, 4R) 4-benzamido--1-(2-(2,2, the 2-trifluoroacetamido) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 83: (2S, 4R) 4-benzamido--1-(2-(tert-butoxycarbonyl is amino) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 84: (2S, 4R) 4-benzamido--1-(2-(dimethylamino) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 85: (2S, 4R) 4-benzamido--1-(2-formamido group ethanoyl) tetramethyleneimine-2-formic acid;
Compound 86: (2S, 4R) 4-benzamido--1-(1H-imidazoles-2-carbonyl) tetramethyleneimine-2-formic acid;
Compound 87: (2S, 4R) 4-benzamido--1-(1H-pyrazoles-5-carbonyl) tetramethyleneimine-2-formic acid;
Compound 88: (2S, 4R) 4-benzamido--1-(1H-imidazoles-5-carbonyl) tetramethyleneimine-2-formic acid;
Compound 89: (2S, 4R) 1-(2-glycyl)-4-(picoline amido) tetramethyleneimine-2-formic acid;
Compound 90: (2S, 4R) 1-(2-glycyl)-4-(nicotinoyl is amino) tetramethyleneimine-2-formic acid;
Compound 91: (2S, 4R) 1-(2-glycyl)-4-(different nicotinoyl is amino) tetramethyleneimine-2-formic acid;
Compound 92: (2S, 4R) 1-(2-glycyl)-4-(pyrimidine-5-formamido group) tetramethyleneimine-2-formic acid;
Compound 93: (2S, 4R) 1-(2-glycyl)-4-(the 2-fluorobenzoyl is amino) tetramethyleneimine-2-formic acid;
Compound 94: (2S, 4R) 1-(2-glycyl)-4-(the 3-fluorobenzoyl is amino) tetramethyleneimine-2-formic acid;
Compound 95: (2S, 4R) 1-(2-glycyl)-4-(the 4-fluorobenzoyl is amino) tetramethyleneimine-2-formic acid;
Compound 96: (2S, 4R) 1-(2-glycyl)-4-(the 2-toluyl is amino) tetramethyleneimine-2-formic acid;
Compound 97: (2S, 4R) 1-(2-glycyl)-4-(the 3-toluyl is amino) tetramethyleneimine-2-formic acid;
Compound 98: (2S, 4R) 1-(2-glycyl)-4-(the 4-toluyl is amino) tetramethyleneimine-2-formic acid;
Compound 99: (2S, 4R) 1-(2-glycyl)-4-(the 4-methoxybenzoyl is amino) tetramethyleneimine-2-formic acid;
Compound 100: (2S, 4R) 1-(2-glycyl)-4-(the 3-methoxybenzoyl is amino) tetramethyleneimine-2-formic acid;
Compound 101: (2S, 4R) 1-(2-glycyl)-4-(4-(2-hydroxybenzoyl) amino) tetramethyleneimine-2-formic acid;
Compound 102: (2S, 4R) 1-(2-glycyl)-4-(3-(2-hydroxybenzoyl) amino) tetramethyleneimine-2-formic acid;
Compound 103: (2S, 4R) 1-(2-glycyl)-4-(2-phenyl kharophen) tetramethyleneimine-2-formic acid;
Compound 104: (2S, 4R) 1-(2-glycyl)-4-(2-oxo-2-phenylethyl is amino) tetramethyleneimine-2-formic acid;
Compound 105: (2S, 4R) 1-(2-glycyl)-4-(phenyl amino) tetramethyleneimine-2-formic acid;
Compound 106: (2S, 4R) 1-(2-glycyl)-4-(phenmethyl is amino) tetramethyleneimine-2-formic acid;
Compound 107: (2S, 4R) 1-(2-glycyl)-4-(phenyl sulfonamido) tetramethyleneimine-2-formic acid;
Compound 108:N-((3R, 5S) 1-(2-glycyl)-5-(1H-tetrazolium-5-yl) tetramethyleneimine-3-yl) BM;
Compound 109:N-((3R, 5S) 1-(2-glycyl)-5-(1H-imidazoles-2-yl) tetramethyleneimine-3-yl) BM;
Compound 110:N-((3R, 5S) 1-(2-glycyl)-5-(5-methyl isophthalic acid H-imidazoles-2-yl) tetramethyleneimine-3-yl) BM;
Compound 111:N-((3R, 5S) 1-(2-glycyl)-5-(5-sec.-propyl-1H-imidazoles-2-yl) tetramethyleneimine-3-yl) BM;
Compound 112:N-((3R, 5S) 1-(2-glycyl)-5-(
Figure BDA0000152435510000431
azoles-2-yl) tetramethyleneimine-3-yl) BM;
Compound 113:N-((3R, 5S) 1-(2-glycyl)-5-(5-sec.-propyl azoles-2-yl) tetramethyleneimine-3-yl) BM;
Compound 114:N-((3R, 5S) 1-(2-glycyl)-5-(5-methyl
Figure BDA0000152435510000433
azoles-2-yl) tetramethyleneimine-3-yl) BM;
Compound 115:N-((3R, 5S) 1-(2-glycyl)-5-(4-methyl
Figure BDA0000152435510000434
azoles-2-yl) tetramethyleneimine-3-yl) BM;
Compound 116:N-((3R, 5S) 1-(2-glycyl)-5-(1H-pyrazoles-5-yl) tetramethyleneimine-3-yl) BM;
Compound 117:N-((3R, 5S) 1-(2-glycyl)-5-(3-sec.-propyl-1H-pyrazoles-5-yl) tetramethyleneimine-3-yl) BM;
Compound 118: N-((3R, 5S) 1-(2-glycyl)-5-(3-methyl isophthalic acid H-pyrazoles-5-yl) tetramethyleneimine-3-yl) BM;
Compound 119:N-((3R, 5S) 1-(2-glycyl)-5-(1H-1,2,4-triazole-5-yl) tetramethyleneimine-3-yl) BM;
Compound 120:N-((3R, 5S) 1-(2-glycyl)-5-(3-methyl isophthalic acid H-1,2,4-triazole-5-yl) tetramethyleneimine-3-yl) BM;
Compound 121:N-((3R, 5S) 1-(2-glycyl)-5-(3-sec.-propyl-1H-1,2,4-triazole-5-yl) tetramethyleneimine-3-yl) BM;
Compound 122:N-((3R; 5S) 1-(2-glycyl)-5-(1; 3,4-
Figure BDA0000152435510000435
diazole-2-yl) tetramethyleneimine-3-yl) BM;
Compound 123:N-((3R; 5S) 1-(2-glycyl)-5-(5-methyl isophthalic acid; 3,4-
Figure BDA0000152435510000436
diazole-2-yl) tetramethyleneimine-3-yl) BM;
Compound 124: (2S, 4R) 4-benzamido--1-(2-(4,5-dihydro-1H-imidazoles-2-base is amino) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 125: (2S, 4R) 1-(2-(1H-imidazoles-2-base is amino) ethanoyl)-4-benzamido-tetramethyleneimine-2-formic acid;
Compound 126: (2S, 4R) 1-(2-(1H-pyrazoles-5-base is amino) ethanoyl)-4-benzamido-tetramethyleneimine-2-formic acid;
Compound 127: (2S, 4R) 4-benzamido--1-(2-(pyridine-2-base is amino) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 128: (2S, 4R) 4-benzamido--1-(2-(pyrimidine-4-base is amino) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 129: (2S, 4R) 4-benzamido--1-(2-(pyrimidine-2--amino) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 130: (2S, 4R) 1-(2-(the 1H-imidazol-4 yl is amino) ethanoyl)-4-benzamido-tetramethyleneimine-2-formic acid;
Compound 131: (2S, 4R) 4-benzamido--1-(2-(3-phenyl urea groups) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 132: (2S, 4R) 4-benzamido--1-(2-(3-methyl urea groups) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 133: (2S, 4R) 4-benzamido--1-(2-(3-sec.-propyl urea groups) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 134: (2S, 4R) 4-benzamido--1-(2-(methyl sulfonamido (sulfonamido)) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 135: (2S, 4R) 4-benzamido--1-(2-(phenyl sulfonamido) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 136: (2S, 4R) 4-benzamido--1-(2-(1-methylethyl sulfonamido) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 137: (2S, 4R) 4-benzamido--1-(2-(ethyl sulfonamido) ethanoyl) tetramethyleneimine-2-formic acid;
Compound 138: (2S, 4R) 1-(2-glycyl)-4-(4-phenyl
Figure BDA0000152435510000441
azoles-2-yl) tetramethyleneimine-2-formic acid;
Compound 139: (2S, 4R) 1-(2-glycyl)-4-(5-phenyl
Figure BDA0000152435510000442
azoles-2-yl) tetramethyleneimine-2-formic acid;
Compound 140: (2S, 4R) 1-(2-glycyl)-4-(5-phenyl-1H-imidazoles-2-yl) tetramethyleneimine-2-formic acid;
Compound 141: (2S, 4R) 1-(2-glycyl)-4-(4-phenyl-1H-imidazoles-2-yl) tetramethyleneimine-2-formic acid;
Compound 142: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-(furans-3-yl) tetramethyleneimine-2-methane amide;
Compound 143: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-(piperidin-4-yl) tetramethyleneimine-2-methane amide;
Compound 144: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-(
Figure BDA0000152435510000451
azoles-4-yl) tetramethyleneimine-2-methane amide;
Compound 145: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-(different
Figure BDA0000152435510000452
azoles-4-yl) tetramethyleneimine-2-methane amide;
Compound 146: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-(
Figure BDA0000152435510000453
azoles-2-yl) tetramethyleneimine-2-methane amide;
Compound 147: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-phenmethyl tetramethyleneimine-2-methane amide;
Compound 148: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-(pyridin-4-yl methyl) tetramethyleneimine-2-methane amide;
Compound 149: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-(pyridin-4-yl) tetramethyleneimine-2-methane amide;
Compound 150: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-(pyridine-2-yl) tetramethyleneimine-2-methane amide; And
Compound 151: (2S, 4R) 1-(2-glycyl)-4-benzamido--N-(pyridin-3-yl) tetramethyleneimine-2-methane amide.
The present invention also comprises isomer and/or enantiomer (2S for example, the 4S of the above-mentioned compound of enumerating; 2S, 4R; 2R, 4R; 2R, 4S; 3S, 5S; 3S, 5R; 3R, 5R; 3R, 5S) and its esters, ester class, hydrate, and prodrug.
Pharmaceutically-acceptable salts class with The compounds of this invention of acidic moiety can use organic and mineral alkali forms.The suitable salt that utilizes alkali to form comprises metal-salt, for example an alkali metal salt or alkaline earth salt, for example sodium, potassium or magnesium salts; Ammonium salt and organic amine salt; For example utilize morpholine, thiomorpholine, piperidines, tetramethyleneimine, list-, two-or three-low-grade alkylamine (for example ethyl-tertiary butyl-, diethylammonium-, di-isopropyl-, triethyl-, tributyl-or dimethyl propylamine), or single-, two-or the trihydroxy-low-grade alkylamine (for example single-, two-or trolamine) form.Also can form inner salt.Similarly, when compound of the present invention contains basic moiety, can use organic and mineral acid forms salt.For example; Can form salt by following acid: acetate, propionic acid, lactic acid, Hydrocerol A, tartrate, succsinic acid, FUMARIC ACID TECH GRADE, maleic acid, propanedioic acid, phenylglycollic acid, Malic acid, D-, phthalic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid, naphthene sulfonic acid, Phenylsulfonic acid, toluenesulphonic acids and camphorsulfonic acid, and other known pharmaceutically acceptable acid.Also available amino acid, for example Methionin, glycocoll or phenylalanine(Phe) form amino acid addition salt.
The present invention also comprises the prodrug of compound described herein.As as used herein, " prodrug " refers to when to the mammalian hosts administration, produce, take place or discharge the part of compound of the present invention.Prodrug can prepare through the functional group that modification is present in the compound, so that through routine operation or make modification group from the parent compound cracking in vivo.The example of prodrug comprises compound of the present invention described herein; It contains one or more molecular moieties that are attached to hydroxyl, amino, sulfydryl or the carboxyl of compound; When its during to the mammalian hosts administration, it is formed free hydroxyl, amino, sulfydryl or carboxyl respectively by cracking in vivo.The example of prodrug includes, but is not limited to alcohol and acetic ester, manthanoate and the benzoate derivatives of amine functional group in the compound of the present invention.The example of preferred prodrug comprises oxazolidone or imidazolidone prodrug.Ester class prodrug preferably utilizes lower alcohol, for example C 1-6Alcohol forms.The preparation of prodrug and be applied in T.Higuchi and V.Stella; " Pro-drugs as Novel Delivery Systems " (" as the prodrug of new drug delivery system); Vol.14 of the A.C.S.Symposium Series, and Bioreversible carriers in Drug Design), Edward B.Roche; American Pharmaceutical Association and Pergamon Press comes into question in 1987.
On the other hand, the present invention provides the verivate of compound, and more particularly said compound by the protection form.For example, said compound can be at its N-end and/or C-end, and/or amino acid side chain (R therein 1Compound for amino acid side chain) locates to be protected.The example of protection base comprises tBu, Boc, Fmoc, Fm, phenmethyl, Dde and Z, also comprises the compound (for example when it is synthetic by solid-phase synthesis) when being coupled to solid phase.
C. pharmaceutical composition
Compound of the present invention can its pure form as medicine or as pharmaceutical composition, it can be through any acceptable method known in the art, individually or administration in combination.The mixture that can comprise compound of the present invention and one or more pharmaceutically acceptable carriers, thinner, carrier or vehicle according to pharmaceutical composition of the present invention.This compsn can be through preparation with (comprising oral cavity or hypogloeeis) for oral administration or through administered parenterally (comprising vein (i.v.), subcutaneous (s.c.), intramuscular (i.m.), intraperitoneal (i.p.)) administration.Other administration route comprises in epidural, rectum, the nose or percutaneous drug delivery, or sucks through lung.Preferred especially preparation provides the lasting release of compound of the present invention.Compsn is preferably the form of solid-state or liquid formulation, and the method for its preparation is described in " Remington ' s Pharmaceutical Sciences ", the 17th edition usually; Alfonso R.Gennaro (Ed.), Mark Publishing Compan, Easton; PA, U.S.A., 1985.
These compsns contain one or more active compounds of the present invention of significant quantity usually, can contain appropriate carriers so that the dosage form compatible with selected route of administration to be provided.Preferably, carrier is the form of vehicle, thinner, buffer reagent, tension regulator, sanitas and stablizer.Constituting the vehicle of carrier must be compatible with the active drug composition and preferably can stable compound and harmless to the host.
Can use the form of storage storehouse or extended release preparation,, for example be delivered in the blood flow in several hours or a couple of days through the transdermal injection or after depositing (deposition) administration so that the preparation of treatment significant quantity can be in compound or compsn administration.Be suitable for sustained release formulation and comprise biodegradable polymer, for example L-lactic acid, D-lactic acid, DL-lactic acid, NSC 403079, oxyacetic acid and isomer thereof.Similarly, carrier or thinner can comprise any lasting releasable material known in the art, and for example glyceryl monostearate or distearin mix separately or with wax.
Other extended release preparations can include, but is not limited to comprise with at least a compound disclosed herein and liposome, microsphere, emulsion or micella or liquid stabilisers bonded preparation.
The dosage that reaches required compound of the present invention of desired therapeutic effect and compsn will depend on the effectiveness of compound, employed particular composition and selected route of administration.The typical dosage scope of compound is each patient's every day of about 0.001g to 10g.For example, the dosage scope of compound be each patient's every day about 1mg to about 1000mg, each patient's every day of about 10mg about 100mg extremely, or each patient's every day about 50mg.
Optimal dosage regimen is preferably confirmed respectively to each patient by the practitioner.Use will be depended on various factors according to the best dosage regimen of compound of the present invention and pharmaceutical composition, specified disease for example to be treated or illness, expected effect, and patient's age, body weight or weight index, and general physiological situation etc.Administration can one unit dosage form be carried out alleviating acute symptom, or carries out the persistence treatment with the form of multidose in for some time.Perhaps, can use lasting transfusion system or slowly-releasing depot formulation.According to two kinds or more compounds of the present invention or pharmaceutical composition co-administered or with the administration in succession of any order simultaneously.In addition, from prevention purpose, the administration in a similar fashion of compound and compsn.Finally, best dosage regimen will be determined respectively according to each patient by the attending doctor.
D. therepic use
Can promote and/or keep the cell-cell communication that the gap connects mediation according to compound of the present invention.On the one hand; Compound according to the present invention with the cell identical with the target spot of AAP, AAP10, HP5 and/or its functional analogue as target spot, i.e. the compound function that can regulate these cells through the function of excitement or antagonism AAP, AAP10, HP5 and/or its functional analogue.Yet scope of the present invention is not limited to have the compound of specific AAP agonist or antagonist properties.The present invention also relates to be used to treat preparation of drug combination and purposes with the impaired relevant patient's condition of intercellular gap junction communication; And use these method for compositions; For example disclosed like WO 02/077017, " cell-cell communication promotes the new medicine use (New Medical Uses of Intercellular Communication Facilitating compounds) of compound ".
The present invention also provides treatment to have the method with the host of the impaired relevant patient's condition (for example irregular pulse or osteoporosis) of GJIC; Or the prevention host avoids taking place the method with the danger of the impaired relevant patient's condition of GJIC, comprises the compound arbitrary of the present invention of drug treatment significant quantity.Can use individuality to include, but is not limited to animal according to compounds for treating of the present invention; Be preferably Mammals, for example rodent (comprises mouse, rat, hamster, reaches Lagomorph; Rabbit for example), dog, pig, sheep (being generally any domestic animal), and primate.One preferred aspect, the host be the mankind.
Use the example of the patient's condition that compound of the present invention can treat or prevent to include, but is not limited to cardiovascular disorder; Osteoporosis; The airway epithelial inflammation; The honeycomb weave illness; Bladder incontinence; Hearing loss (for example causing) owing to the cochlea disease; The endothelium pathology; Mellitus (I type or II type) and diabetic complication (comprising diabetic retinopathy and diabetic neuropathy); Atherosclerosis; The patient's condition relevant with CNS; Epileptic seizures; Local asphyxia (the for example local asphyxia of cns, spinal cord, brain or brain stem); Dental tissue illness (comprising periodontopathy); Kidney disease; Hematology presentation (for example anaemia, leukopenia, thrombocytopenia and pancytopenia, especially after utilizing cell growth-inhibiting compounds for treating or radiotherapy); Wound (for example the appearance wound and since wound cause go deep into wound etc.); Fracture; Erection problem, urine bladder incontinence; Neuropathic pain; Inferior chronic and chronic inflammatory diseases; Cancer; Marrow and stem cell move and grow failure; During cell and tissue transplantation or the patient's condition that takes place in medical journey operating period of for example operation; The patient's condition that is caused because of excess reactivity oxygen species and/or radical and/or nitrogen protoxide; Conceived disease or illness (for example preeclampsia and premature labor); Infertility, and apoplexy.Also can be used for induced labor (for example through promoting that pitocin is to uterotonic effect) according to compound of the present invention.
One preferred aspect; The present invention provides the antiarrhythmic compounds of pharmacological activity; Being used to treat or preventing during the cardiovascular disorder, during the coronary revascularization and the irregular pulse and the thrombus complication that take place under the analogue, said cardiovascular disorder for example be acute ischemic heart trouble (for example stable angina pectoris, unstable angina pectoris, Acute Myocardial Infarction), congestive heart failure (for example systole, diastole, high output, hang down output, the right side or left side cardiac failure), congenital heart disease, cor pulmonale, myocardosis, myocarditis and hypertensive heart disease.In specific embodiments; Compound according to the present invention can be used for treatment and/or prevented chronic irregular pulse (for example because sinus node, AV knot, His bundle, the right side or left bundle branch disease cause), and with return to relevant tachyarrhythmia (for example the atrium phase before complex wave, chamber (AV) have a common boundary early win, ventricular premature contraction, atrial fibrillation, auricular flutter, paroxysmal supraventricular tachycardia, sino-atrial node reentry property tachycardia, chamber (AV) tie reciprocal tachycardia and nonsustained ventricular tachycardia).In addition, compound according to the present invention can be used for alleviating pathological condition, for example ventricular tachycardia, ventricular fibrillation and atrial fibrillation, and the conduction of velocity that wherein slows down is an important factor.Can be individually dosed according to compound of the present invention; Or with other antiarrhythmic compounds combination medicine-feedings; Said antiarrhythmic compounds does, for example one type of medicine (for example lignocaine), II class medicine (for example metoprolol or Proprasylyte), III class medicine (for example amiodarone or sotalol) or IV class medicine (for example verapamil).
Also can be used for treatment or prevent one or more following diseases according to compound of the present invention: the arrhythmia of turning back; Ventricle turn back (ventricular reentry) (for example betide Acute Myocardial Infarction; Chronic myocardial infarction; During stability stenocardia and the unstable angina pectoris); Infectivity or autorhymicity myocardosis; Atrial fibrillation; Repolarization alternately; The monotype ventricular tachycardia; T-ripple electrical alternations; Chronic irregular pulse; The convergent force of heart tissue reduces; Thrombosis etc.
After the function of other that the endothelium gap connects that cell-cell communication relates to is the coordination of injured, blood vessel generation, endothelial cell growth and aging, vasoconstriction reaction; The migratory behaviour of endotheliocyte (people such as Christ; Braz.J Med Biol.Res., 33,423-429 (2000)).Therefore, compound according to the present invention is used in (for example body kinematics, tachycardia) during the patient's condition that metabolic demand increases, and during local asphyxia, promotes vasoreactive conduction and improve blood supply.
Compound according to the present invention can be used for the mammiferous tissue of this treatment of needs or the cytoprotective of organ.Cytoprotective refers to reduce, prevent or alleviate and the related symptom of deleterious cellular swelling.Particular organization and the organ that can benefit from this method comprise that receiving fibrous capsule limits and influencer, for example heart or kidney.Also comprise and the related tissue of bone, for example brain, spinal cord and marrow.Compound of the present invention can be used for preventing or treating the local asphyxia damage in the mammalian organs that needs this kind treatment, and said organ comprises for example heart, cns, kidney, gi tract, liver, lung and four limbs.
On the other hand, the present invention provides compounds for treating or prevents the purposes with hematology presentation behind cell growth-inhibiting compounds for treating or the radiotherapy.After the treatment of 5-fluor-uracil (5-FU) cell growth-inhibiting, in the patient, can be observed impaired hemoposieis and recover.This comprises the recovery that lacks the peripheral blood counting, comprises serious neutropenia, has the skein cell minimizing and has the erythrocytic serious anaemia of unusual periphery, and serious thrombocytopenia.In addition, in marrow, observe medullary cell structure and HPC content (graininess scavenger cell colony forming unit (CFU-GM), the quick-fried formula of red blood corpuscle form unit (BFU-E), blended colony forming unit (CFU-mix) and whole colony forming unit (CFU-C)) and reduce 5-8 doubly.(referring to people such as for example Montecino-Rodriguez, Blood, 96,917-924, (2000); People such as Presley, Abstract#55, IGJC 2005, Whistler, Canada (2005)).Comprise in this respect usually and the treatment and the prevention of the related general clinical condition of iatrogenic pancytopenia of the present invention.
Compound according to the present invention can be used for treatment or preventing osteoporosis disease.Known GJIC is important at bone forming on.Can through for example in the activation analysis of standard scleroblast the active increase of scleroblast assess the effect of compound, this standard scleroblast activation analysis is measured in the presence of said compound, formation of calcium ripple and/or alkaline phosphatase activity in the scleroblast.Alkaline phosphatase activities also can be used for providing the active measurement of scleroblast of use standard colorimetric analysis.
Preferably, be administered in the individuality of needs with the treatment significant quantity according to one or more compounds of the present invention or pharmaceutical composition.As as used herein, " treatment significant quantity " refers to reduce the amount of the symptom of particular condition or symptom, and preferably this amount makes the host's with this patient's condition or symptom physiological response normalizing.The minimizing of symptom or the normalizing of physiological response can use the conventional method in this area to measure, and can change with particular condition or symptom.On the one hand; The treatment significant quantity of one or more compounds or pharmaceutical composition is for recovering measurable physiological parameter to identical with the host's who does not have this patient's condition or symptom parameter basically value (preferably in ± 30% scope; More preferably in ± 20% scope, more preferably in ± 10% scope) amount.
Significant quantity will consider that effectiveness, patient's age and physique, the body weight of medicine for example, the factors such as pharmacokinetic properties of medicine confirm by the technician, and generally speaking, medicine will be organized according to each patient or patient and write out a prescription.Yet the significant quantity of compound can be at least about 10 μ g/kg body weight/day, for example at least about 100 μ g/kg body weight/day, and at least about 300 μ g/kg body weight/day, and at least about 1000 μ g/kg body weight/day.On the other hand, the significant quantity of compound or dipolymer can be about 100mg/kg body weight/day, for example about at most 50mg/kg body weight/day, and about at most 10mg/kg body weight/day at most.The significant quantity of expecting compound will be about 100 μ g/kg body weight/day, about 300 μ g/kg body weight/day or about 1000 μ g/kg body weight/day.
E. bioanalysis
Be called herein in " the standard A AP site combines test ", preferred compound of the present invention can combine, and preferred specificity is bonded to tissue, cell or cell part.This test can detect and choose wantonly the combination of quantitative motif compound, for example AAP, AAP10, HP5 or its functional analogue.In a preferred embodiment, the compound function regulator (being the function of compound excitement or antagonism irregular pulse peptide) of tissue, cell or cell part for this reason.In another embodiment, compound can be the regulator (being that compound is the agonist or the antagonist of acceptor) of the acceptor of antiarrhythmia peptide.In addition, in addition preferred compound according to the present invention can demonstrate function well as the regulator of gap junction communication (for example as AAP agonist or antagonist).On the one hand, this compound can be used as antiarrhythmic medicine.
Be called as herein in " standard myocardial cell's analysis ", preferred agonist compound of the present invention can provide endocellular electricity to lead coefficient (Gj), and Gj with AAP is identical basically for it, or greater than the Gj of AAP.Preferred agonist compounds can provide the Gj lower than the Gj of AAP (for example to hang down about 10% at least; Or hang down about 20% at least); And/or the ability of blocking-up AAP is with the Gj of normalizing local asphyxia cell, even Gj gets back to and the essentially identical value that in non local ischemic cell, records.In addition preferred compound according to the present invention is called as in " arrhythmia analysis of standard calcium-initiation ", at infusion CaCl herein 2After, in the mouse body, can increase the time that AV blocks.Be called herein in " standard of the delayed conduction that metabolic stress causes is separated atrium overburden model ", compound of the present invention can prevent the cardiac conduction of various multi-form metabolic stresses (for example local asphyxia, hypoglycemia or acidismus) under existing to slow down.Be called in this article in " analysis of turning back property of standard ventricle ", compound of the present invention also can reduce the generation of the arrhythmia of turning back, or big or small the reducing of observed infarct area.
In some embodiments, according to being called " external plasma stability analysis " here, compound of the present invention can present the good transformation period.In one embodiment, the transformation period that the compound of demonstration good stability has in analysis surpasses about 48 hours, or surpasses 24 hours, or above 12 hours; Or surpass 6 hours, or surpass 3 hours, or above 1 hour; Or surpass 30 minutes, or surpass 20 minutes, or above 15 minutes; Or surpass 10 minutes, or surpass 5 minutes, or above 1 minute.In these embodiments, compound of the present invention can be presented at the stability that increases in the blood.
Can be used for identifying and choose the active particular analysis of quantitative The compounds of this invention wantonly and be further described in hereinafter.
1. the standard plasma stability is analyzed
The present invention is provided at the compound that has the stability of enhancement in external or the body.For example, comprising the compound of the present invention of peptide bond can be by alkylation or otherwise modified with stable compound antagonism enzyme liberating.In addition, compound can comprise one or more D-amino acid.Whether test compounds has enhancement in the standard stability analysis stability is possible.
In the example that external plasma stability is analyzed; The compound incubation is in blood plasma or serum; And with the time sampling of rule; Analyze the amount of quantitative undegradable compound (referring to for example WO 02/077017, its whole disclosures are herein incorporated by reference) through HPLC or LC/MS/MS.Estimate the felicity condition (post, solvent, gradient and temperature) of this analysis, do not have identical RT to guarantee compound peaks and blood plasma peak.This is through injecting compound, blood plasma subsequently, and injects compound and blood plasma jointly, and then optimization LC method parameter is accomplished until obtaining gratifying separation.The contrast plasma sample of peptide containing compound is not handled with the same manner, takes a sample yet and estimates.Sample can include, but is not limited to blank control group, proper concn compound (for example 0.1mg/mL), do not contain the blood plasma of compound, one or more samples when t=0, and at one or more samples in each rule timed interval.Preferably, obtain a plurality of samples with parallel mode.With sample concentration (peak height in mAU or ion counting) with respect to temporal mapping and fit to the function (for example using standard Excel software package) of single index decay.Preferably, use this to analyze measured transformation period and surpass about 30 minutes (for example surpass about 1 hour, or surpass about 3 hours, or surpass about 6 hours, or surpass about 12 hours, or surpass about 24 hours, or above about 48 hours) according to compound of the present invention.
Use standard analysis can check plasma stability in vivo.For example, compound can be administered to Mammals, for example rat through injecting (bolus) and oral (p.o.) (with amount of intravenous injection (i.v.) and all about 1ml/kg of oral (p.o.) administration).Preferably, compound and control sample parallel testing, this control group for example are damping fluid or antiarrhythmia peptide with known stability.At the interval blood sample (for example B.D.5,15,30,60,90,120,180 and 240 minutes, before wherein B.D. shows medicine) of collecting of different time.The amount of compound can use in this area ordinary method quantitative in the sample, for example LC/MS/MS.For example, the compound concentration in the plasma sample can be calculated by the outer standard substance curve of containing 1.00 to 1000nM compound concentration scope.Plasma concentration data with respect to the time can be used for the pharmacokinetics simulation (at WinNonLin 3.5 (Pharsight; Mountain view; CA) in, use non-compartment model analysis), the AUC of gained, Fpo, Clb, t1/2, Cmax and tmax parameter can be confirmed through mode known in the art.
2. the standard myocardial cell analyzes
Compound of the present invention can be measured in the myocardial cell analyzes, after it measures compound administration, and myocardial cell's gap linkage function.In an example,,, separate the myocardial cell of Mammals (the for example heart of guinea pig) through the potting compound protoenzyme according to the Langendorf method.Cell is contacted with compound, and use means known in the art, through patch clamp assessment GJIC.Iuntercellular specific conductance (Gj) uses following formula to calculate:
Figure BDA0000152435510000531
(equation 1)
I wherein P, pulseAnd I P stopsRepresent the electric current in the preceding passive type cell of impulse duration and pulse respectively, Up and Ua represent voltage passive and the active cell.The change of Gj value is analyzed through the relative change of comparing Gj when compound administration.For example, using compound (for example about 10 -8M) stimulate before with during, can be measured as the relative Gj of the function of time.Preferably, compound provides Gj, and the Gj (± 10%) of itself and antiarrhythmia peptide (for example AAP, AAP10, HP5 and functional analogue thereof) is basic identical.In an example, cell is the local asphyxia cell, and compound provides Gj, the Gj of itself and non local ischemic cell basic identical (± 20%, be preferably ± 10%).Other details about carrying out myocardial cell's analysis are provided among the WO 02/077017.
3. the arrhythmia analysis that causes of standard calcium
The peptide that is suitable for being administered to the myocardial cell can be confirmed (according to people such as Lynch (1981), the model of J Cardiovasc.Pharmacol.3:49-60) in the ARR body inner model that calcium causes.Utilize intraperitoneal administration (IP), with ketamine (75mg/kg) and the male CD-1 mouse of MPU-295 (1mg/kg) anesthesia.The i.v. conduit is inserted the tail vein.Through stainless steel ECG electrode is placed on right fore and the left fore, continue record helical pitch II ECG signal.Ground-electrode is placed on the right hind.Use Gould physiograph assembly and po-ne-mah data to obtain software amplification and filtration signal.After between 90 seconds balance period, test compounds is injected into tail vein (in 30 seconds).Test utilizes the mouse of carrier pretreat, with it as control animal.In all experiments, volume injected is 100 μ l/30g mouse.CaCl 2Infusion (30mg/mL, the 0.1mL/min/30g mouse, 100mg/kg/min) after medicine or carrier (0.9% saline water) IV administration 3 minutes the beginning.The time lag that centroid myocyte block takes place is with from CaCl 2Infusion begins to measure until the time of the irregular pulse generation first time.It is interval that block for the first time is defined as a RR, more than or equal to interval 3 times of the RR-during pretreat.For the first time irregular pulse occurs as second stage AV-retardance (intermittence of AV conduction is depleted, it is characterized by the P-ripple of not following the QRS wave group) or second stage SA retardance (RR-of prolongation interval and do not have the QRS-wave group of (preceding) P-ripple in advance).Reacting phase was represented for the time, betided in the mouse of vehicle treatment until second stage AV-retardance.
4. the isolating atrium of the standard overburden model of the delayed conduction that causes of metabolic stress
The peptide that is suitable for being administered to the myocardial cell can be confirmed in external model as people such as Haugan (J.Cardiovasc.Electrophysiol., 16,537-545 (2005)) are said.
Kill rat (300-400g) through the neck bang.Excise heart apace and be transferred in the shallow bid of 37 ℃ of Tyrodes damping fluids that contain the oxygenation modification, this damping fluid contains (in mM): NaCl 136, KCl 4, MgCl 20.8, CaCl 21.8, HEPES 5, MES 5, glucose 6, and pH 7.3.Dissect the left atrium carefully, and obtain the tissue sample of about 2 * 6mm, and be positioned over tissue compartments (volume 5ml) (Steiert Organ Bath, Hugo Sach Electronic, Germany) from left auricle of heart.The Tyrodes damping fluid of 37 ℃ of oxygenations with the speed of 10ml/min, is poured in this chamber in whole research.
Bipolar stimulation electrode (applying the stainless steel of Teflon (Teflon), diameter 75 μ M) is placed on an end of tissue.Use square topped pulse, carry dual threshold (lasting stimulates 0.2ms) via separating element (Universal Isolated Stimulator Unit type 263, Hugo Sachs, Germany), under 1Hz, stimulate with stimulator (Hugo Sachs, 215 types).
Two pure independently iridium microelectrodes (World Precision Instruments, needle point impedance 3.5-4.0M Ω) are placed along the line of the longitudinal axis of the prepared product that is used to write down atrium CV.Distance by stimulating electrode to first and second microelectrode is respectively 1.5-2.0mm and 3.0-4.0mm.Each microelectrode is connected to head-stage prime amplifier (signal 10 * amplification).Prime amplifier is connected to the biopotential amplifier module, and this biopotential amplifier module is connected to data acquisition system through Hugo Sachs PLUGSYS.Signal filters under 1kHz and sampling under 10kHz.
After between 30 minutes balance period, begin with the leg speed of 1Hz.In the preceding 20 minutes record phase (baseline period), the chamber is poured the Tyrodes damping fluid of 37 ℃ of oxygenations, and pH 7.3.Then in other 20 minutes (during the pretreat), compound (the for example compound of the lysine-mimetic of modification of the present invention, AAP, AAP10 or control) is added into the perfusion damping fluid.At pretreat after 20 minutes, change perfusion into 37 ℃ and do not contain glucose, the Tyrodes damping fluid of oxygenate not, pH 7.3 (containing or do not contain target compound) 40 minutes (during the metabolic stress).
During metabolic stress, with the relatively change of conduction of velocity of untreated control group.In untreated prepared product, during 40 minutes of metabolic stress, conduction reduces 15-45%.In some embodiments, compare with compd A AP, AAP10, HP5 or its functional analogue, compound according to the present invention is in 40 minutes, but prevention of metabolic stress cause delayed conduction, and promptly compound can be kept normal conduction at metabolic stress between the emergence period.
5. analysis of Hematology Changes
Also can test compound of the present invention, with measure its 5-fluor-uracil (5-FU) bone marrow proliferation is caused stress after, add the effect of quick-recovery.Handled male rat 4 days with 5-FU (75-100nmol/kg intraperitoneal administration).Before 5-FU handles (the 0th day),, and after the 5-FU administration first time, collected blood sample at the 4th, 8,12,16,20,24,28 day from the terminal collection of tail blood sample.Carry out the mensuration of peripheral blood counting (granulocyte, lymphocyte, red corpuscle, thrombocyte, netted hemocyte) and plasma hemoglobin.After identifying window, during following, repeat research with compounds for treating of the present invention with serious pancytopenia.
F. the preparation of exemplary compounds
Following non-limiting example only supplies to illustrate the present invention.It will be understood by a person skilled in the art that have the equivalent processes of many not examples and alternative still to form part of the present invention.
Lysine-mimetic compounds of the present invention can be synthetic next synthetic through solid phase or liquid phase.Thus; Can be with reference to many other documents, people such as Fields for example, " solid-phase peptide synthetic principle and put into practice (Principles and practice of solid-phase peptide synthesis) "; Synthetic Peptides (2002, the 2 editions).
Response diagram 1 is described the compound of formula III, (2S, 4R)-4-benzamido--1-(2-(4,5-dihydro-1H-imidazoles-2-base is amino) ethanoyl) tetramethyleneimine-2-formic acid exemplary synthetic, wherein Y ' is NHR 3And R 3Not hydrogen.
Response diagram 1
Figure BDA0000152435510000561
The substituted amino acid derivative of different N-can be used for other compound of synthetic formula III, and wherein Y ' is NHR 3And R 3Not hydrogen.For example; 2-chloro-1H-imidazoles or 4-bromo-1H-imidazoles glycocoll soluble in water capable of using is handled (for example, according to being recorded in European Journal of Medicinal Chemistry (1989), 24 (6); The step of 623-5); Form 2-(1H-imidazoles-2-base is amino) acetate or 2-(the 1H-imidazol-4 yl is amino) acetate respectively, it can be used to synthesize (2S then with the mode of similar reaction process 1; 4R)-1-(2-(1H-imidazoles-2-base amino) ethanoyl)-4-benzamido-tetramethyleneimine-2-formic acid or (2S, 4R)-1-(2-(the 1H-imidazol-4 yl is amino) ethanoyl)-4-benzamido-tetramethyleneimine-2-formic acid.Compound; (2S for example; 4R)-4-benzamido--1-(2-(pyridine-2-base amino) ethanoyl) tetramethyleneimine-2-formic acid, (2S; 4R)-4-benzamido--1-(2-(pyrimidine-4-base amino) ethanoyl) tetramethyleneimine-2-formic acid and (2S, 4R)-4-benzamido--1-(2-(pyrimidine-2--amino) ethanoyl) tetramethyleneimine-2-formic acid can be synthetic by 2-(pyridine-2-base is amino) acetate, 2-(pyrimidine-4-base is amino) acetate and 2-(pyrimidine-2--amino) acetate respectively similarly.
Perhaps, glycine derivative can be synthetic according to reaction process 2.
Reaction process 2
Figure BDA0000152435510000571
In above-mentioned example, the 2-that is produced (1H-pyrazoles-5-base is amino) acetate can use method shown in the reaction process 1, be used to synthesize (2S, 4R)-1-(2-(1H-pyrazoles-5-base is amino) ethanoyl)-4-benzamido-tetramethyleneimine-2-formic acid.
The compound of formula II (wherein A and R 1Form the 5-20 unit heteroaryl that contains one or more N, O or S atom with its bonded carbon), can utilize suitable carboxylic acid to synthesize according to reaction process 1 as raw material.For example; (2S; 4R)-4-benzamido--1-(1H-imidazoles-2-carbonyl) tetramethyleneimine-2-formic acid, (2S; 4R)-4-benzamido--1-(1H-pyrazoles-5-carbonyl) tetramethyleneimine-2-formic acid or (2S, 4R)-4-benzamido--1-(1H-imidazoles-5-carbonyl) tetramethyleneimine-2-formic acid can use 1H-imidazoles-2-formic acid, 1H-pyrazoles-5-formic acid or 1H-imidazoles-5-formic acid to synthesize respectively according to reaction process 1.
Another of the compound of reaction process 3 explanation formula IIIs is exemplary synthetic, and wherein Y ' is NHR 3And R 3Not hydrogen.In this example, (2S, 4R)-4-benzamido--1-(2-(3-phenyl urea groups) ethanoyl) tetramethyleneimine-2-formic acid, R 3Be C (O) NR 6R 7
Reaction process 3
Figure BDA0000152435510000572
Different isocyanic ester (for example methyl isocyanate or n-Isopropyl isocyanate) can be applicable to the synthetic of reaction process 3; With other ureas of producing formula III ((2S for example; 4R)-4-benzamido--1-(2-(3-methyl urea groups) ethanoyl) tetramethyleneimine-2-formic acid or (2S, 4R)-4-benzamido--1-(2-(3-sec.-propyl urea groups) ethanoyl) tetramethyleneimine-2-formic acid).
Reaction process 4 explanations (2S, 4R)-(compound of formula III, wherein Y ' is NHR to tetramethyleneimine-2-formic acid to 4-benzamido--1-(2-(methyl sulfonamido) ethanoyl) 3And R 3Be S (O) R 6) exemplary synthetic.
Reaction process 4
Begin by other SULPHURYL CHLORIDE (for example ethyl sulfonyl chloride or propane-2-SULPHURYL CHLORIDE); Use method shown in the reaction process 4; Different the sulphonamide ((2S for example that can prepare formula III; 4R)-4-benzamido--1-(2-(ethyl sulfonamido) ethanoyl) tetramethyleneimine-2-formic acid or (2S, 4R)-4-benzamido--1-(2-(1-methylethyl sulfonamido) ethanoyl) tetramethyleneimine-2-formic acid).
For example, according to reaction process 5, can synthesize the compound of formula III, wherein k is 1 or 2 (for example (2S, 4R)-1-(the amino propionyl group of 3-)-4-benzamido-tetramethyleneimine-2-formic acid).
Reaction process 5
Figure BDA0000152435510000582
Reaction process 6 shows the compound of formula III, (2S, 4R)-1-(2-glycyl)-(wherein Z ' is (CH to 4-(phenyl amino) tetramethyleneimine-2-formic acid 2) m-C 6-20Aryl and m are 0) exemplary synthetic.
Reaction process 6
Figure BDA0000152435510000591
Likewise, the compound of reaction process 7 explanation formula IIIs, (2S, 4R)-(wherein Z ' is (CH to tetramethyleneimine-2-formic acid to 1-(2-glycyl)-4-(phenmethyl is amino) 2) m-C 6-20Aryl and m are 1) exemplary synthetic.
Reaction process 7
Figure BDA0000152435510000592
Wherein Z ' is (CH 2) m-5-20 unit's heteroaryl and m are 0 or 1 compound, also can use suitable raw material to prepare according to the method for reaction process 6 or 7.
Reaction process 8 shows the compound of formula III, (2S, 4R)-(wherein Z ' is C (O) (CH to 1-(2-glycyl)-4-(2-phenyl kharophen) tetramethyleneimine-2-formic acid 2) m-C 6-20Aryl and m are 1) exemplary synthetic.
Reaction process 8
Wherein Z ' is C (O) (CH 2) m-C 6-20Aryl and m are 2, or Z ' is C (O) (CH 2) m-5-20 unit's heteroaryl and m are 1 or 2 compound, also can use suitable raw material to prepare according to the method for reaction process 8.
The compound of formula III, wherein Z ' is S (O) 2(CH 2) m-C 6-20Aryl or S (O) 2(CH 2) m-5-20 unit heteroaryl, for example, can be synthetic according to reaction process 9, reaction process 9 explained (2S, 4R)-1-(2-glycyl)-4-(phenyl sulfonamido) tetramethyleneimine-2-formic acid synthetic.
Reaction process 9
Reaction process 10 shows (2S; 4R)-1-(2-glycyl)-4-(4-phenyl
Figure BDA0000152435510000603
azoles-2-yl) tetramethyleneimine-2-formic acid (compound of formula II; Wherein B is that the acid amides bioisostere is (referring to for example Tetrahedron:Asymmetry; 14 (20), 3141-3152; 2003) exemplary synthesizing).
Reaction process 10
Figure BDA0000152435510000611
Another compound of reaction process 11 explanation formula II; (2S; 4R)-1-(2-glycyl)-4-(5-phenyl
Figure BDA0000152435510000612
azoles-2-yl) tetramethyleneimine-2-formic acid (wherein B is different acid amides bioisostere) synthetic (referring to for example Journal of Heterocyclic Chemistry (1998); 35 (6), 1533-1534).
Reaction process 11
Another compound again of formula II (wherein B is the acid amides bioisostere); (2S; 4R)-1-(2-glycyl)-4-(4-phenyl-1H-imidazoles-2-yl) tetramethyleneimine-2-formic acid synthetic; Be shown in reaction process 12 (referring to for example Tetrahedron:Asymmetry, 14 (20), 3141-3152; 2003; Journal of Medicinal Chemistry, 44 (18), 2990-3000; 2001).
Reaction process 12
Figure BDA0000152435510000621
The compound of reaction process 13 explanation formula II, N-(synthesize by (3R, 5S)-1-(2-glycyl)-5-(1H-tetrazolium-5-yl) tetramethyleneimine-3-yl) the exemplary of BM (wherein E is the carboxylic acid bioisostere).
Reaction process 13
Figure BDA0000152435510000622
Reaction Figure 14 shows another method, but the compound through its synthesis type II, and wherein E is that the carboxylic acid bioisostere is (referring to for example Journal of Medicinal Chemistry, 44 (18), 2990-3000; 2001).
Reaction Figure 14
Figure BDA0000152435510000631
Except being shown in the N-((3R of reaction process 14; 5S)-1-(2-glycyl)-5-(5-methyl isophthalic acid H-imidazoles-2-yl) tetramethyleneimine-3-yl) outside the BM; Compound with formula II of different carboxylic acid bioisosteres can be according to this method; Use different bromine carbonyl reagents to synthesize (N-((3R for example; 5S)-1-(2-glycyl)-5-(1H-imidazoles-2-yl) tetramethyleneimine-3-yl) BM or N-((3R, 5S)-1-(2-glycyl)-5-(5-sec.-propyl-1H-imidazoles-2-yl) tetramethyleneimine-3-yl) BM).
Reaction process 15-17 explanation is used for another illustrative methods of the compound of synthesis type II, and wherein E is the carboxylic acid bioisostere.
Reaction process 15
Figure BDA0000152435510000632
Reaction process 16
Figure BDA0000152435510000641
Reaction process 17
Figure BDA0000152435510000642
Except the compound that is shown in reaction process 15-17, the compound with different carboxylic acids bioisostere can synthesize through changing reagent according to these methods.For example; Different bromide reagent can be used in the reaction process 15 and (for example to generate N-((3R, 5S)-1-(2-glycyl)-5-(
Figure BDA0000152435510000643
azoles-2-yl) tetramethyleneimine-3-yl) BM); Different dimethylamino ketals can be used for (for example generating N-((3R in the reaction process 16; 5S)-1-(2-glycyl)-5-(4H-1; 2,4-triazole-3-yl) tetramethyleneimine-3-yl) BM or N-((3R, 5S)-1-(2-glycyl)-5-(5-sec.-propyl-4H-1; 2,4-triazole-3-yl) tetramethyleneimine-3-yl) BM); And different ortho ester can be used for reaction process 17 and (for example generates N-((3R; 5S)-1-(2-glycyl)-5-(1; 3,4-
Figure BDA0000152435510000644
diazole-2-yl) tetramethyleneimine-3-yl) BM).
1. the universal synthesis method of peptide
Compound of the present invention can use disclosed compound method to prepare, for example, and in WO98/11125 (its complete disclosure is herein incorporated by reference).Said compound method will produce elementary peptide (primary peptide) or have the similar peptide prod of trifluoroacetic acid root antagonism ionic, and they are suitable for preparing medicine.Yet, in some cases, preferably the trifluoroacetic acid radical ion is converted into pharmaceutically acceptable or preferred ion (like acetate moiety) antagonism IX through for example ion-exchange chromatography.Perhaps, elementary peptide or the lyophilize repeatedly of similar peptide prod and be dissolved in the Hydrogen chloride to obtain the hydrochloride of purifying.
Device and synthetic schemes
When using solid phase method class hour; The peptide class of modification is used 9-fluorenyl methoxy carbonyl (Fmoc) and tert-butoxycarbonyl (Boc) or the amino protection base of other suitable N-; And side chain functionalities such as allyl group, Alloc, Dde, Z for example, be equipped with the Vilaterm groove that is used for filtering polypropylene filter synthetic in bulk.When using liquid technology, in entire synthesis process, the peptide of modification uses standard equipment to synthesize.
Solvent
Solvent DMF (N, dinethylformamide, Riedel de-
Figure BDA0000152435510000651
Germany) is through being filled with strong cation-exchanging resin (Lewatit S 100MB/H strong acid; Bayer AG Leverkusen, Germany) post is by purifying, and before use; Through adding 3; 4-dihydro-3-hydroxyl-4-oxo-1,2,3-phentriazine (Dhbt-OH) is analyzed unhindered amina; If unhindered amina exists, be yellow (Dhbt-O-negatively charged ion).Solvent DCM (methylene dichloride; AG, Riedel de- Germany) directly do not using under the purifying.Acetonitrile (HPLC level, Lab-Scan, Dublin Ireland) is not directly using under the purifying.
Amino acid
The amino acid of Fmoc-and Boc-protection is by Advanced ChemTech (ACT), and Bachem and NeoMPS buys, and is the form of suitable side chain protected.
Benzoic acid derivative
Benzoic acid derivative is buied by Aldrich, and be not further purified use down.
Coupling reagent
Coupling reagent DIC (DIC) is buied from (Riedel de-
Figure BDA0000152435510000653
Germany).
Solid support
Peptide is synthesized on available from the TentaGel (for example SRam) of Advanced ChemTech and Rapp and PS (for example PAM resin).
Catalyzer and other reagent
Diisopropylethylamine (DIEA) is from Aldrich; Germany buys; Quadrol is buied from Fluka; Hydrazine, piperidines and pyridine are from Riedel-de
Figure BDA0000152435510000654
Frankfurt, and Germany buys.4-(N, N-dimethylamino) pyridine (DMAP) is by Fluka, and the catalyzer of the coupled reaction that relates to symmetric anhydride is buied and be used as in Switzerland.Dithioglycol and thioanisole (Thioanisol) are from Riedel-de Frankfurt, and Germany buys.3,4-dihydro-3-hydroxyl-4-oxo-1,2,3-phentriazine (Dhbt-OH), I-hydroxybenzotriazole (HOBt) are (HOAt) by Fluka, and Switzerland buys.
Couling process
Suitably first amino acid of the amino acid of N--protection generation can be in DMF be symmetric anhydride by coupling; And but amino acid original position coupling subsequently is HOBt or HOAt ester; This ester is by means of the DIC in DMF, processed by the amino acid of suitable N--amido protecting and HOBt or HOAt.Under 80 ℃, through ninidrine experimental check acylation reaction, to prevent experimental session Fmoc deprotection (B.D.Larsen, A.Holm, Int.J.Pept.Protein Res., 43,1-9 (1994)).
The deprotection effect (Fmoc and Fm) of protection base
(1 * 5 and 1 * 10min.) handles the DMF solution of the deprotection of Fmoc and Fm base through 20% piperidines, then carries out with DMF washing (5 * 15ml, each 5min), until adding till Dhbt-OH back to the DMF that discharges detects less than yellow.
The deprotection effect (Boc and tBu) of protection base
The deprotection of Boc and tBu base is through DCM solution v/v (2 * 2min of 50%TFA; 1 * 30min) handles; Then with DCM (6 * 2min) washings; Then (2 * 2min) washings, then (3 * 2min) handle, and follow at last to wash with DMF that (6 * 2min) carry out with the DMF solution v/v of 5%DIEA with DMF.
Aloc and allylic deprotection
With 3 normal Pd (PPh 3) 4Be dissolved in the CHCl of 15-20ml 3, AcOH, NMM (37: 2: 1) solution, be added into peptide resin.Processing at room temperature continues 3 hours, follows to be blown into N 2Stream makes it pass through mixture.
The coupling of Hobt-ester class
The amino acid of 3 normal N-alpha-amino group protections is dissolved among the DMF with 3 normal HOBt and 3 normal DIC, then is added in the resin.
Preformed symmetric anhydride
The amino acid of six normal N-alpha-amino group protections is dissolved among the DCM and is cooled to 0 ℃.Added DIC (3 equivalent) and sustained reaction 10 minutes.Go down to desolventize in vacuum, residuum is dissolved among the DMF.Solution is added in the resin immediately, then adds 0.1 normal DMAP.
Use TFMSA from resin cracking compound
At room temperature; Utilize 90% trifluoroacetic acid (TFA; Riedel-de
Figure BDA0000152435510000671
Frankfurt; Germany), (TFMSA Aldrich), 2% dithioglycol, 4% thioanisole v/v, handled peptidyl-resin 30-60 minute 4% trifluoromethanesulfonic acid.Utilize the TFA flushing through filtering resin, under reduced pressure steam and remove filtrating and washing lotion.Utilize the ether debris, dry from trifluoroacetic acid-water-cooled freeze-drying.Utilize performance liquid chromatography (HPLC) to analyze thick lyophilisation product, utilize electron spray(ES) ion massspectrum method (ESMS) to identify.
Use TFA from resin cracking compound
At room temperature; With 95% trifluoroacetic acid (TFA; Riedel-de
Figure BDA0000152435510000672
Frankfurt; Germany)-and water (v/v) or 95%TFA and 5% dithioglycol (v/v), handled peptidyl-resin 2 hours., under reduced pressure steam and remove filtrating and washing lotion through filtering resin with the 95%TFA-water washing.Utilize the ether debris, dry from acetate-water-cooled freeze-drying.Utilize performance liquid chromatography (HPLC) to analyze thick lyophilisation product, utilize electron spray(ES) ion massspectrum method (ESMS) to identify.
The preparation HPLC condition
The preparative hplc utilization is equipped with the VISION Workstation (PerSeptive Biosystem) of AFC2000 automatic fraction collector/self-actuated sampler to carry out.VISION-3 software is used for instrument control and data obtain.
Post
Kromasil (EKA Chemicals) KR100-10-C8
Figure BDA0000152435510000673
C-8,10 μ m; CER2230; 250 * 50; 8mm or VYDAC 218TP101550;
Figure BDA0000152435510000674
C-18,10-15 μ m, 250 * 50mm.Employed buffer system comprises the MQV solution of A:0.1%TFA; B:0.085%TFA, 10%MQV, 90%MeCN.Flow velocity is that 35-40ml/min and column temperature are 25 ℃.Under 215nm and 280nm, carrying out UV detects.To the suitable gradient of indivedual peptide optimizations.
Analysis mode HPLC condition
Gradient HPLC analyzes and uses Hewlett Packard HP 1100 HPLC systems to carry out, and this system is made up of HP 1100 four-stage pumps, HP 1100 self-actuated samplers, HP 1100 thermocolumns and HP 1100 multiwavelength detectors.The Hewlett Packard Chemstation (rev.A.06.01) that is used for LC software is used for instrument control and data obtain.For analysis mode HPLC; Use different posts according to circumstances; Like VYDAC 238TP5415, C-18,5 μ m;
Figure BDA0000152435510000675
or Jupiter, Phenomenex00F-4053-E0; 5 μ m; C-18;
Figure BDA0000152435510000676
150 * 4,6mm etc.Buffer system comprises the MQV solution of A:0.1%TFA; B:0.085%TFA, 10%MQV, 90%MeCN.Flow velocity is 1ml/min.Preferred column temperature is 40 ℃.UV detects and under 215nm, carries out.As stated, to the suitable gradient of indivedual peptide optimizations.
Mass spectrum
Peptide be dissolved in supergradient methyl alcohol (Labscan, Dublin, Ireland), Milli-Q water (Millipore, Bedford, MA) and formic acid (Merck, Damstadt, Germany) (50: 50: 0.1v/v/v), obtain the boundary in 1 and 10mg/ml between concentration.Through ESI-TOF-MS, use the LCT mass spectrograph (Micromass, Manchester UK), analyze peptide solution (20ml) in the straight polarity pattern, tolerance range is+/-0.1m/z.
Solid phase synthesis
In all were synthetic, dried resin placed and is equipped with the Vilaterm groove that supplies filtering polypropylene filter.Resin is swelling in DMF.As stated, the first amino acid coupling is preformed symmetric anhydride or preactivated HOBt ester.As stated, following amino acid is coupled to preformed HObt ester in regular turn.Except as otherwise noted, all couplings all continue at least 2 hours.In all cases, benzoic acid derivative is coupled to the side chain amino functionality on the lysine-mimetic amino acid, all uses preformed HObt-ester to carry out.As stated, final peptide prod is analyzed from the solid carrier cracking and through HPLC and MS.
In all cases, benzoic acid derivative functionalised into carboxylic acid and passes through the DIC among the THF, and the original position coupling produces the HOBt ester.
All couplings all continue at least 2 hours.As previously mentioned, through under 80 ℃, carrying out the ninidrine experiment, the inspection acylation.After completion is synthesized, utilize DMF (3 * 15ml, each 1min), DCM (3 * 15ml, each 1min), ether (3 * 15ml, each 1min) to wash peptide-resin and drying under vacuum.Then as stated from resin cleavage of peptide and lyophilize.
After using the preparation HPLC purifying as stated, collect peptide prod and pass through the identity (identity) that ES-MS confirms peptide.
Exemplary liquid phase is synthetic
With the amino acid of due care or hydroxyl-or Thiovanic acid with not protecting carboxylic acid (1 equivalent), DIC (1 equivalent) and HOBt (1 equivalent) to be dissolved among the DMF.Activation is after 1 hour in advance, and the lysine-mimetic structural unit (LM) that will have the due care of unprotected amino (1.1 equivalent) adds with TEA (1.3 equivalent), at room temperature stirs the mixture and spends the night.
Reaction mixture is evaporated to drying, and resistates is dissolved in the ETHYLE ACETATE.Utilize (1) aqueous hydrochloric acid (0.1M) and (2) aqueous sodium hydroxide solution (0.1M) and (3) water extraction ETHYLE ACETATE to remove unnecessary raw material.Utilize MgSO 4(exsiccant) handled organic phase, filters and be evaporated to drying.
If the protection base then uses TFA/DCM based on tBu,,,, make the protected amino deprotection of residue of LM if the protection base then uses hydrazine based on Dde if the protection base then uses piperidines/DCM based on fluorenyl if the protection base then uses the Pd tetrahydrobenzene based on phenmethyl.After accomplishing deprotection reaction (1-2 hour), evaporation reaction mixture is to dry.Be dissolved among the DMF with the ether debris and with 1.3 equivalent TEA, finally be added in substituted phenylformic acid (1 equivalent) solution, this solution has been used DMF solution-treated and the in advance activation of DIC (1 equivalent) and HOBt (1 equivalent).Coupled reaction continues to spend the night.
Reaction mixture is evaporated to drying and resistates is dissolved in ETHYLE ACETATE.Extract ETHYLE ACETATE mutually with (2) aqueous sodium hydroxide solution (0.1M) with (3) water with (1) aqueous hydrochloric acid (0.1M), to remove excessive raw material.Utilize MgSO 4(exsiccant) handled organic phase, filters and be evaporated to drying.
If the protection base then uses TFA/DCM based on tBu,,,, make the basic deprotection of residue protection if the protection base then uses hydrazine based on Dde if the protection base then uses piperidines/DCM based on fluorenyl if the protection base then uses the Pd tetrahydrobenzene based on phenmethyl.After accomplishing deprotection reaction (1-2 hour), evaporation reaction mixture is to dry.Use the ether debris, and be dissolved in the TFA/ water, use the preparation HPLC purifying.As stated, use the preparation HPLC purifying after, collect peptide prod and confirm the identity of peptide through ES-MS.
2. the solid phase synthesis of compound 2: (2S, 4R) 1-(2-amino-ethanoyl)-4-benzoyl-amido-tetramethyleneimine-2-formic acid
With PAM-resin (Advanced Chemtech) swelling in DMF, with the DMF solution washing of 5% triethylamine (TEA), and with the DMF washing, till interpolation Dhbt-OH back in the DMF that discharges is detected less than yellow.(2S, 4R) Boc-4Amp (Fmoc)-OH is obtained symmetric anhydride by following coupling.
(2S, 4R) Boc-4Amp (Fmoc)-OH is dissolved among the DCM and is cooled to 0 ℃ with 3 equivalents.Added DIC (1.5 equivalent) and sustained reaction 10 minutes.Go down to desolventize and resistates is dissolved among the DMF in vacuum.Solution is added in the resin immediately, then adds 0.1 normal DMAP.Coupling continues to spends the night.Remove excessive coupling reagent with the DMF washing.With the DMF solution-treated of 20% piperidines (1 * 5 and 1 * 10min.), carry out the deprotection of Fmoc base, then with the DMF washing, until adding till Dhbt-OH back in the DMF that discharges detects less than yellow.
Benzoic coupling is undertaken by following step.3 equivalent phenylformic acid are dissolved among the DMF with 3 equivalent HOBt and 3 equivalent DIC, and then are added into resin.Coupling continues to spends the night.Remove excessive coupling reagent with the DMF washing.Before Boc base deprotection, use the DCM process resin.(2 * 2min, 1 * 30min) handles, and carries out the deprotection of Boc base, then with the DCM washing, and then with the DMF washing, with the DMF solution v/v processing of 5%DIEA, then washs with DMF at last subsequently with the DCM solution v/v of 50%TFA.
The coupling of Boc-Gly-OH is undertaken by following step.3 equivalent Boc-Gly-OH are dissolved among the DMF with 3 equivalent HOBt and 3 equivalent DIC, then are added in the resin.Coupling continues 2 hours.Through with the DMF washing, remove excessive coupling reagent.Repeat coupling and continue to spend the night.Before the solid support cleavage of peptide, wash peptide resin with DCM, then with the ether washing, last dried in vacuum.
As mentioned below, carry out dipeptides cracking from the PAM-resin.With trifluoroacetic acid (TFA; Riedel-de
Figure BDA0000152435510000701
) handles peptide-resin; After 10 minutes, at room temperature, add the trifluoromethanesulfonic acid (TFMSA that volume is equivalent to TFA TV 10%; Aldrich), sustained reaction is 2 hours.Resin with the TFA washing and filtering.From TFA solution, be settled out raw material through adding ether.Collect raw material, be brown oil.Then water extraction diethyl ether solution evaporates water.Raw material with the whole amounts of preparation HPLC (VydacC18-post) purifying: the aqueous solution of buffer A: 0.1%TFA; Buffer B: 90%AcCN; 0.1%TFA; 9.9% water.Flow velocity: 35ml/min.Gradient: 0-47min 100%A to 75%A (linearity).HPLC purity: 99%.MS: calculated value M+H=291.12; Measured value M+H=291.7.
3. the liquid phase of compound 2 is synthetic
At NaHCO 3(58.64g, in water 0.698mol) (625mL) solution, by part add N-BOC-anti--4-amino-L-proline methyl ester hydrochloride (50g, 0.1745mol, CNH Technologies, 98%), then add EtOAc (500mL).Mixture is cooled to 0 ℃.Under 0 ℃, in 25 minutes, add Benzoyl chloride 99min. (20.26mL, EtOAc 0.1745mol) (100mL) solution.Reaction mixture stirs 1h down at 0 ℃.Separate phase, with the EtOAc aqueous phase extracted of 2 * 200mL.With the HCl of 200mL 1N, the saturated NaHCO of 100mL 3The organic moiety that the brine wash of solution, 100mL merges is used MgSO 4Drying, concentrate obtain 60.67g (2S, 4R)-the 1-tertiary butyl-2-methyl-4-benzamido-tetramethyleneimine-1, the 2-dicarboxylic acid esters, (productive rate is 99.8% for heavy oil; By remaining EtOAc adjustment, then productive rate is 94%). 1H NMR (CDCl 3, δ, ppm; Two conformers): 7.78-7.7 (m, 2H), 7.56-7.4 (m, 3H), 6.25-6.1 (m, 1H), 4.8-4.67 (m, 1H); 4.51-4.41 (m, 0.4H), 4.34 (dd, J=7,7Hz, 0.6H), 3.97-3.84 (m, 1H); 3.76 (s, 3H), 3.52 (dd, J=11,4Hz, 0.6H), 3.39 (dd, J=11; 4Hz, 0.4H), 2.47-2.21 (m 2H), 1.46 (s, 3.6H), 1.43 (s, 5.4H).MS (m/z, positive ESI, M+Na): 371.
Will (2S, 4R)-the 1-tertiary butyl-2-methyl-4-benzamido-tetramethyleneimine-1, (60.19g contains 5.6%EtOAc to the 2-dicarboxylic acid esters; 0.1631mol) be dissolved in Et 2Among the O (100mL), the vaporising under vacuum solvent is to remove remaining EtOAc.The oil of remnants is dissolved in Et 2Among the O (100mL).Add the Et of 2N HCl 2O solution (700mL) (gentle heat release; Begin deposition after about 5 minutes).21h stirs the mixture under the room temperature.At this moment, add the Et of 200mL 2N HCl 2O solution, 24h in addition stirs the mixture.Filtering precipitate, with 500mL ether washing, dry 24h under vacuum, room temperature, obtain 46.03g (2S, 4R)-methyl 4-benzamido-tetramethyleneimine-2-manthanoate hydrochloride (productive rate 99%). 1H NMR (CD 3OD, δ, ppm): 7.91-7.84 (m, 2H), 7.6-7.44 (m, 3H), 4.78 (t, J=8.5Hz; 1H), 4.69-4.59 (m, 1H), 3.77 (dd, J=12,6.6Hz, 1H), 3.52 (dd; J=12,5Hz, 1H), 2.67-2.5 (m, 2H) .MS (m/z, positive ESI, M+H): 249.
To BOC-Gly-OH (28.13g, 0.1606mol) and I-hydroxybenzotriazole (0.1686mol, 25.64g; Contain 11.12wt%H 2O) in THF (1.3L) solution, add N-(3-dimethyl aminopropyl)-N '-ethyl-carbodiimide hydrochloride (0.1686mol, 32.328g) (flask A).The 4h that at room temperature stirs the mixture then stops to stir, and makes the sedimentation of oiliness resistates.In other flask (flask B), in 15 minutes, with NaOH (0.1606mol; The 5N solution of 32mL) be added into (2S, 4R)-(0.1606mol is in THF 45.73g) (0.52L) suspension-s for methyl 4-benzamido-tetramethyleneimine-2-manthanoate hydrochloride.The 10min that at room temperature stirs the mixture, most of during this period solid dissolves.With the solution of the HOBt ester for preparing among the flask A at room temperature, in 15 minutes, be added into flask B, stay the oiliness resistates.With the resistates among the 250mL THF washing flask A, decant THF solution and it is added in the mixture the flask B from heavy oil.Stirred reaction mixture 40min at room temperature.Add water (500mL), enriched mixture is to remove THF (～550mL residual volume) under vacuum.Add EtOAc (500mL), add salt solution (300mL).Separate phase, with the EtOAc aqueous phase extracted of 2 * 300mL.With the 1N HCl of 2 * 250mL, the saturated NaHCO of 2 * 250mL 3The organic moiety that solution and 150mL brine wash merge is then at MgSO 4Last dry, concentrate obtain 48.31g (2S, 4R) methyl-4-benzamido--1-(2-(tert-butoxycarbonyl is amino) ethanoyl) tetramethyleneimine-2-manthanoate is spumescence solid (productive rate 74%). 1H NMR (CDCl 3, δ, ppm; Two conformers): 7.81-7.72 (m, 2H), 7.57-7.39 (m, 3H), 6.41 (d, J=6Hz, 0.8H), 6.25 (d; J=6Hz, 0.2H), 5.32 (b r.s, 1H), 4.88-4.74 (m, 1H), 4.65 (t, J=7Hz; 1H), 4.11-3.86 (m, 2H), 3.83-3.78 (m, 1H), 3.76 (s, 3H), 3.69-3.56 (M; 1H), 2.65-2.3 (m, 2H), 1.43 (s, 9H) .MS (m/z, positive ESI, M+Na): 428.
Under-1 to 1 ℃, in 15min to (2S; 4R) methyl-4-benzamido--1-(2-(tert-butoxycarbonyl-amino) ethanoyl) tetramethyleneimine-2-manthanoate (23.33g; 0.0575mol) methyl alcohol (450mL) solution in, add NaOH (0.2875mol, the 2N aqueous solution of 144mL).2.5h stirs the mixture under-5 to-1 ℃.Under-3 to 1 ℃, in 25min, add HCl (0.2875mol, the 2N aqueous solution of 144mL).Under vacuum, distill MeOH, then add 500mL EtOAc.Water is saturated with NaCl, separates phase.With 2 * 250mL EtOAc aqueous phase extracted, the EtOAc solution that merges is used MgSO 4Drying, concentrate obtain 22.54g (2S, 4R) 4-benzamido--1-(2-(tert-butoxycarbonyl is amino) ethanoyl) tetramethyleneimine-2-formic acid is the white foam shape solid (EtOAc that contains 6.6wt%; By remaining EtOAc adjustment, productive rate is 94%). 1H NMR (CD 3OD, δ, ppm): 7.87-7.79 (m, 2H), 7.58-7.42 (m, 3H), 4.81-4.7 (m 1H), 4.69-4.56 (m, 1H), 4.05-3.72 (m, 3H), 3.67-3.49 (m, 1H), 2.64-2.28 (m, 2H), 1.43 (s, 9H) .MS (m/z, positive ESI), M+H:392; M+Na:414.
With (2S, 4R) 4-benzamido--1-(2-(tert-butoxycarbonyl is amino) ethanoyl) tetramethyleneimine-2-formic acid (21.97g; The EtOAc that contains 6.6wt%; 0.0524mol, by remaining EtOAc adjustment) be dissolved in two
Figure BDA0000152435510000721
in the alkane (100mL).Evaporating solvent under the vacuum is to remove remaining EtOAc.With resistates be dissolved in anhydrous two
Figure BDA0000152435510000722
in the alkane (200mL), 10-12 ℃ add down HCl (100mL of prepared fresh～two
Figure BDA0000152435510000723
3.6N solution in the alkane).Solution is heated to room temperature (beginning deposition behind about 2min).Stirred reaction mixture 21h at room temperature, add this moment 30mL～3.6N HCl solution, with mixture restir 5.5h.Use N 2Air pressure, the solid of filtering-depositing is with 4 * 25mL two
Figure BDA0000152435510000724
Alkane washing, dry 24h under vacuum, room temperature obtains the crude product of 18.7g, is white solid.Crude product is dissolved among the i-PrOH (104mL), in 1h, adds 210mL ether (when adding ether, forming deposition immediately).The 1h that stirs the mixture uses N 2Air pressure filtration is with 3 of 2 * 50mL: 1Et 2The O-i-PrOH solution washing, dry 24h under vacuum, room temperature, at 40 ℃ of following dry 48h, obtain 15.7g (2S, 4R)-1-(2-glycyl)-4-benzamido-tetramethyleneimine-2-formate hydrochlorate. 1H NMR (DMSO-d6, δ, ppm, two conformers): 8.77 (d, J=7Hz, 0.8H), 8.71 (d; J=7Hz, 0.2H), 8.68-7.95 (br, 2H), 7.92-7.83 (m, 2H); 7.59-7.43 (m, 3H), 4.87-4.79 (m, 0.2H), 4.68-4.54 (m, 0.8H); 4.54-4.44 (m, 1H), 4.0-3.47 (m, 4H), 2.47-2.12 (m, 2H) .HRMS calculated value: C 14H 18N 3O 4(M+H): 292.1297, measured value: 292.1294.
4. compound 64-68 and 70-78's is synthetic
Under nitrogen environment, with ice-cooled, with (2S; 4R)-4-benzamido--1-(2-(tert-butoxycarbonyl amino) ethanoyl) tetramethyleneimine-2-formic acid (0.05g, 0.1mmol), I-hydroxybenzotriazole monohydrate (Aldrich, 0.021g; 0.15mmol, 1.2 equivalents) and 1-(3, the 3-dimethyl aminopropyl)-3-ethyl carbon two imide salt hydrochlorate (Aldrich; 0.029g, 0.15mmol, 1.2 equivalents) and be dissolved in acetonitrile (15mL).In 2 hour period, temperature is increased to room temperature gradually, at room temperature stir the mixture subsequently and spend the night.Reaction soln is cooled to 0 ℃ once more, and (0.1mL), cooling and stirring continues 30 minutes to the aqueous solution of the corresponding amine of interpolation 25-30% (by the pure reagent preparation available from Aldrich), then at room temperature stirs 2 hours.(5mL) is added in the reaction mixture with acetonitrile, in vacuum removal of volatiles matter.(EMD, 0.040-0.063mm) (launch solvent: purifying semi-solid state resistates 3-5% gradient methyl alcohol-methylene dichloride) obtains corresponding acid amides, productive rate 80-87% to chromatogram with silica gel.
In nitrogen environment, the product that abovementioned steps is obtained is dissolved in anhydrous methylene chloride (10mL), adds the ethereal solution (1mL) of 1M hydrochloric acid (Aldrich), keeps temperature to be lower than 30 ℃ simultaneously.Stirred reaction mixture spends the night in nitrogen environment.Filtering precipitate washs with methylene dichloride (2mL) and ether (2mL), and is dry under high vacuum, obtains the hydrochloride of corresponding compound 64-68 and 70-78, and productive rate 75-84% and purity are at least 98%.
5. compound 80 is synthetic: (2S, 4R)-1-(2-kharophen ethanoyl)-4-benzamido-tetramethyleneimine-2-formic acid
Under the room temperature, in nitrogen environment, (the 2S in stirring; 4R) 1-(2-amino-ethanoyl)-4-benzoyl-amido-tetramethyleneimine-2-formic acid (0.05g, 0.17mmol) and triethylamine (Aldrich) (0.19mL, 1.37mmol; 8 equivalents) in acetone (3mL) solution; Slowly add diacetyl oxide (0.13mL, 1.37mmol, 8 equivalents).Stirred the mixture 3 hours, and monitored with LCMS simultaneously.During completion; Removing volatiles under vacuum matter is also used preparation HPLC (post: Xterra MSC1850 * 250mm; 10u uses 40/60 to 90/10 methanol gradient (aqueous solution of the methanol solution of 0.1% formic acid and 0.1 formic acid)) the purifying resistates, obtain 0.020g (productive rate 35%) title product; Be white solid, its solubleness in organic solvent is limited.
6. compound 81 is synthetic: (2S, 4R)-4-benzamido--1-(2-(methylamino) ethanoyl) tetramethyleneimine-2-formic acid
In nitrogen environment, under 0 ℃, to (2S; 4R)-and methyl 4-benzamido-tetramethyleneimine-2-manthanoate (the synthetic midbody of compound 2) (0.05g, 0.20mmol), 1-(3, the 3-dimethyl aminopropyl)-3-ethyl-carbodiimide hydrochloride (Aldrich) (0.043g; 0.22mmol; 1.1 I-hydroxybenzotriazole monohydrate (Aldrich) (0.030g, 0.22mmol, 1.1 equivalents) and 2-(tert-butoxycarbonyl (methyl) amino) acetate (Aldrich) (0.038g equivalent); 0.20mmol) anhydrous methylene chloride (10mL) solution in, add N-methylmorpholine (0.05mL).In 2 hour period, make reaction mixture be warmed to room temperature, and stirred overnight at room temperature.Removing volatiles under vacuum matter; And through silica gel (EMD; 0.040-0.063mm) chromatogram (expansion solvent: 3-5% gradient ethanol/methylene) purifying resistates; Obtain 0.064g (productive rate 75%) coupling product, (2S, 4R)-methyl 4-benzamido--1-(2-(tert-butoxycarbonyl (methyl) amino) ethanoyl) tetramethyleneimine-2-manthanoate.
Under 0 ℃, in nitrogen environment, in 5 minutes, (0.064g in methyl alcohol 0.15mmol) (5mL) solution, adds 2N aqueous sodium hydroxide solution (0.38mL, 0.75mmol, 5 equivalents) to above-mentioned acid amides.Reaction is with LCMS monitoring and completion in 2 hours.Under 0 ℃, in 5 minutes, add 2N aqueous hydrochloric acid (Aldrich) (0.38mL, 0.75mmol, 5 equivalents).Distillating carbinol under vacuum.Add ETHYLE ACETATE (10mL) and water (1mL).Water is saturated with sodium-chlor, and separates phase.With ETHYLE ACETATE (2 * 10mL) aqueous phase extracted.The organic moiety that merges with dried over mgso, and concentrating, (2S, 4R)-4-benzamido--1-(2-(tert-butoxycarbonyl (methyl) amino) ethanoyl) tetramethyleneimine-2-formic acid, it was not used under purifying down in the step to obtain white foam shape product.
In nitrogen environment, will be dissolved in by the acid that abovementioned steps obtains in the anhydrous methylene chloride (10mL), and add the ethereal solution (1mL) of 1M hydrochloric acid (Aldrich), keep temperature to be lower than 30 ℃ simultaneously.Stirred reaction mixture spends the night under nitrogen environment.Filter formed throw out, with methylene dichloride (2 mL), ether (2mL) washing, and dry under high vacuum.Be further purified product through preparation HPLC (post: XterraMSC18 19 * 150mm, use 5% to 95% methanol gradient (aqueous solution of the methanol solution of 0.1% formic acid and 0.1% formic acid)), obtain the title product of 0.026g (3 step productive rate 38%).
7. compound 82 is synthetic: (2S, 4R)-4-benzamido--1-(2-(2,2, the 2-trifluoroacetamido) ethanoyl) tetramethyleneimine-2-formic acid
At room temperature, in nitrogen environment, to (the 2S that stirs; 4R) 1-(2-amino-ethanoyl)-4-benzoyl-amido-tetramethyleneimine-2-formic acid (compound 2,0.05g, 0.17mmol) and triethylamine (Aldrich) (0.048mL; 0.34mmol; In the solution of acetone 2 equivalents) (3mL), slowly add trifluoroacetic anhydride (0.024mL, 0.17mmol).Mixture stirred 1.5 hours, and carefully monitored through LCMS.When accomplishing; Removing volatiles under vacuum matter is also with preparation HPLC (post: XterraMSC18 50 * 250mm; 10u; Use 5% to 90% methanol gradient (aqueous solution of the methanol solution of 0.1% formic acid and 0.1% formic acid)) the purifying resistates, obtain the title product of 0.012g (productive rate 18%).
8. compound 84 is synthetic: (2S, 4R)-4-benzamido--1-(2-(dimethylamino) ethanoyl) tetramethyleneimine-2-formic acid
At room temperature, to (2S, 4R) (compound 2,0.05g in methyl alcohol 0.17mmol) (3mL) solution, add 37% formalin (Aldrich) (0.1mL) to 1-(2-amino-ethanoyl)-4-benzoyl-amido-tetramethyleneimine-2-formic acid.Under this temperature, stir the gained mixture 3 hours, then be cooled to 0 ℃, and in 5 minutes, by a part interpolation sodium cyanoborohydride (Aldrich) (0.043g, 0.69mmol, 4 equivalents).After at room temperature stirring 1 hour; Under vacuum, remove and desolvate; And with preparation HPLC (post: XTerra MS C18,5u, 19 * 150mm; Use 5% to 95% methanol gradient (aqueous solution of the methanol solution of 0.1% formic acid and 0.1% formic acid)) the purifying solid residue, obtain 0.017g (productive rate 31%) title product.
9. compound 85 is synthetic: (2S, 4R)-4-benzamido--1-(2-formamido group ethanoyl) tetramethyleneimine-2-formic acid
Under 0 ℃, with diacetyl oxide (Acros) (0.32mL, 3.4mmol; 10 equivalents) dropwise be added into (2S, 4R) 1-(2-amino-ethanoyl)-4-benzoyl-amido-tetramethyleneimine-2-formic acid (compound 2,0.1g; 0.34mmol, 1 equivalent) formic acid solution (J.T.Baker) (1mL).After accomplish adding, make reaction mixture be warmed to room temperature, and restir 24 hours.With TLC and LCMS monitoring reaction mixture.Add the diacetyl oxide (0.32mL, 3.4mmol, 10 equivalents) of additional quantity, and stirred reaction mixture 24 hours at room temperature.Add frozen water (1mL) and removing volatiles under vacuum matter, produce the oily crude product, its can be further through HPLC (post: Waters Atlantis 19 * 150mm, use the H of 0.1% formic acid 2O/MeOH solution, the 20-40%MeOH gradient is in 15 minutes) purifying, obtain 0.031g (29%) title product.
The above-mentioned universal method that provides is used for the exemplary compounds of synthetic table 1.
Table 1
Figure BDA0000152435510000771
Figure BDA0000152435510000781
Figure BDA0000152435510000791
Figure BDA0000152435510000801
G. bioanalysis data
1. compound is to the ARR effect of calcium initiation
According to the antiarrhythmic effect of compound of the present invention, in the ARR model (according to people such as Lynch, J.Cardiovasc.Pharmacol. (1981), the model of 3:49-60) that calcium causes, detect.Utilize intraperitoneal administration (IP), with ketamine (Ketamine) (75mg/kg) and MPU-295 (medetomidine) (1mg/kg) anaesthetize male CD-1 mouse.The i.v. conduit is inserted the tail vein.Through stainless steel ECG electrode is placed on right fore and the left fore, continue record helical pitch II ECG signal.Ground-electrode is placed on the right hind.Use Gould physiograph assembly and po-ne-mah data to obtain software, amplify and the filtration signal.After between 90 seconds balance period, test compounds is injected into tail vein (in 30 seconds).Test utilizes the mouse of carrier (0.9% salt solution) pretreat, with it as control animal.In all experiments, volume injected is 100 μ l/30g mouse.CaCl 2Infusion (30mg/mL, the 0.1mL/min/30g mouse, 100mg/kg/min) after medicine or carrier IV administration 3 minutes the beginning.The time lag that the dirty block of centroid takes place is with from CaCl 2Infusion begins to measure until the time of the arrhythmia event generation first time.It is interval that block for the first time is defined as a RR, more than or equal to interval 3 times of a RR-during pretreat.For the first time arrhythmia event occurs as second stage AV-retardance (intermittence of AV conduction is depleted, it is characterized by the P-ripple of not following the QRS wave group) or second stage SA retardance (RR-of prolongation interval and do not have the QRS-wave group of P-ripple in advance).
All fates all detect the mouse utilize carrier (0.9% salt solution) pretreat, with as the measurement standard of not treating control level in the animal.In all experiments, volume injected is 100 μ L.Centroid is restrained the time lag of not normal beginning, with from CaCl 2Infusion begins to measure until the time that block first time incident takes place, and this block is defined as the depletion at intermittence of SA or AV conduction, it is characterized in that P-ripple activation (SA retardance) that postpones or the P-ripple (AV retardance) of not following the QRS wave group.Time lag apart from AV retardance beginning provides in following table 2.
Table 2
Compound The time (sec.) of AV retardance
Salt solution (control group) 62-78
2 134.7
6 117.9
26 122.8
52 135.6
54 121.7
56 128.1
64 111.7
65 115.2
66 122.7
67 134.4
68 143.8
80 111.5
81 123.2
82 113.8
83 110.9
84 108.8
Table 2 data presented shows, with chemical compound lot pretreat mouse of the present invention, can cause at CaCl 2In the mouse body behind the infusion, the consistence of AV residence time increases.Therefore compound of the present invention presents antiarrhythmic characteristic.
2. compound is to the effect of the atrium delayed conduction of metabolic stress initiation
Under metabolic stress, keep conduction ability can as people such as Haugan (J.Cardiovasc.Electrophysiol., 2005:16:537-545) said, in external model, detect.Kill rat (300-400g) through the neck bang.Excise heart apace and be transferred in 37 ℃ of shallow bids that contain the Tyrodes damping fluid that oxygenation modifies, this damping fluid contains (in mM): NaCl 136, KCl 4, MgCl 20.8, CaCl 21.8, HEPES 5, MES 5, glucose 6, and pH 7.3.Dissect the left atrium carefully, obtain the tissue sample of about 2 * 6mm, be positioned over tissue compartments (volume 5ml) (Steiert Organ Bath, Hugo Sach Electronic, Germany) from left auricle of heart.37 ℃ of Tyrodes damping fluids with the speed of 10ml/min, are poured in this chamber in whole research.
Bipolar stimulation electrode (applying the stainless steel of Teflon (Teflon), diameter 75 μ M) is placed on an end of tissue.Use square topped pulse, carry dual threshold (lasting stimulates 0.2ms) via separating element (Universal Isolated Stimulator Unit type 263, Hugo Sachs, Germany), under 1Hz, stimulate with stimulator (Hugo Sachs, 215 types).
Two pure independently iridium microelectrodes (World Precision Instruments, needle point impedance 3.5-4.0M Ω) are placed along the line of the longitudinal axis of the prepared product that is used to write down atrium CV.Distance by stimulating electrode to first and second microelectrode is respectively 1.5-2.0mm and 3.0-4.0mm.Each microelectrode is connected to head-stage prime amplifier (signal 10 * amplification).Prime amplifier is connected to the biopotential amplifier module, and this biopotential amplifier module is connected to data acquisition system through Hugo Sachs PLUGSYS.Signal filters under 1kHz and sampling under 10kHz.
After between 30 minutes balance period, begin with the leg speed of 1Hz.In the preceding 20 minutes record phase (baseline period), the chamber is poured the Tyrodes damping fluid of 37 ℃ of oxygenations, and pH 7.3.Then during other 20 minutes (during the pretreat), specimen (compound 2) or control group are added into the perfusion damping fluid.At pretreat after 20 minutes, change perfusion into 37 ℃ of no glucose, the Tyrodes damping fluid of oxygenation not, pH 7.3 (containing or do not contain target compound), 40 minutes (during the metabolic stress).These result of experiment show with picture in Fig. 1.
According to Fig. 1, in containing the prepared product of control, conduction of velocity reduces by 22%.By contrast, in the prepared product of handling with compound 2, with baseline, the atrium conduction of velocity does not change.
According to data shown in Figure 1, with the pretreat of The compounds of this invention to isolated rat atrial bar (atrial strip), the prevention of metabolic property cardiac conduction that stress cause slows down significantly.Heart disease, for example atrial fibrillation, auricular flutter, ventricular tachycardia and ventricular fibrillation are all with the characteristic that exists for of abnormal heart delayed conduction.Therefore, through effect, expect that compound of the present invention can bring into play the arrhythmia effect to cardiac conduction.
3. plasma stability analysis
For the plasma stability of compound of the present invention is described, with the concentration of 1 μ M, under 37 ℃, with compound of the present invention incubation (1: 1 blood plasma: pH, 7.4 damping fluids) in male rat blood plasma.After 3 hours, with cold acetonitrile termination reaction.With solution centrifugal, and, use following HPLC condition: Thermo Hypersil-Keystone Aquasil C18 post (50mm * 2.1mm, 5 μ M), room temperature with LC-MS clear liquid analytically; Solvent orange 2 A: the aqueous solution of 0.1% formic acid; The acetonitrile solution of solvent B:0.1% formic acid; The solvent gradient: in 2.5 minutes, 100%A to 50%A to 10%A, and got back to 100%A and balance 1.5 minutes once more in 1.5 minutes; Flow velocity: 0.8mL/min.The per-cent (the LC-MS signal area counting with 3 hours incubation samples is counted divided by the area of time=0) that the computerized compound is residual.These result of experiment are summarized in the following table 3.
Table 3
Compound Residual %
2 93
64 27
65 87
66 100
67 100
68 96
69 92
70 93
71 90
72 88
73 95
80 100
81 100
82 34
83 100
84 100
85 107
4. metabolic stability analysis
In order to explain that compound crosses the stability under (first pass) (fs) metabolism at head, with compound of the present invention, under 37 ℃, with the protein concn of 1 μ M concentration and 0.5mg/mL, with male rat hepatomicrosome incubation.Behind the 15min, with cold acetonitrile termination reaction.Centrifugal solution and with LC-MS clear liquid analytically uses the described HPLC condition of above-mentioned the 3rd joint.Residual per-cent is counted divided by the area of time=0 o'clock by 15 minutes incubation sample LC-MS areas counting and is calculated, and the compound transformation period uses first order reaction kinetics to derive.Analyze based on this, compound 2,64,65,66,67,68,69,70,71,72,73,80,81,82,83 and 84 has the transformation period greater than 30 minutes in the male rat hepatomicrosome.
5. dog infarction size and reperfusion arrhythmia model
Describe like people such as Hennan (J.Exp.Pharmacol.Ther., 317,236-43 (2006)),, carry out the test of compound 2 standing 60-minute coronary occlusion and 4 hours dabbling again dogs.Before perfusion again, compound 2 intravenous injections (IV) administration 10 minutes, to inject+mode of IV infusion, dosage: 0.25 μ g/kg injects+0.19 μ g/kg/hr infusion (n=6); 2.5 μ g/kg injects+1.9 μ g/kg/hr infusions (n=7); 25 μ g/kg inject+19 μ g/kg/hr infusions (n=6); 75 μ g/kg inject+57 μ g/kg/hr infusions (n=5); Vehicle Control group (n=7).At quantitative ventricular premature beat (PVC ' s) between flush phase again.Four or above continuous P VC ' s be defined as ventricular tachycardia (VT).Compare with control group (23.0 ± 6.1), twice dosage the highest of compound 2 reduces total incidence (1.7 ± 0.8 of VT significantly; 2.2 ± 1.4 incidents; P＜0.05).Behind the compound 2 of the maximum dose level that is administered twice, total PVC ' s drops to 2.0 ± 0.7% and 1.8 ± 0.8% by 11.1 ± 1.6% of control animals significantly.Infarction size is represented with the per-cent of left ventricle, in twice dosage the highest of compound 2, drops to 7.9 ± 1.5 and 7.1 ± 0.8% (p＜0.05) by 19.0 ± 3.5 of control group significantly.These results confirm that compound of the present invention is the effective antiarrhythmic compounds with Cardioprotective effect.
6. cell in vitro expands and the dyestuff absorption model
There is the peptide of cytoprotection in the external model that cell expansion that local asphyxia causes and dyestuff absorb, to identify.In this experiment, the effect that 2 pairs of fluorexon dyestuffs of research compound absorb, the metabolism that said fluorexon dyestuff absorbs by the C6 neuroglial cytoma of the cultivation that connects the protein 43 over-expresses suppresses to cause.Cell under controlled conditions, during the local asphyxia (SI) that stimulates, fluorexon (200 μ M) existed down, by incubation 40 minutes.Behind the incubation,, measure its absorption to fluorexon with incident fluorescence microscopic examination cell.The incubation of C6 cell in the SI substratum absorbs dyestuff and increases to 5 times that are higher than control value.Absorb combined thing 2 and be dose-dependent inhibition, and (with respect to carrier, but the SI initiation reaction reduces by 32% relatively when compound 2 concentration are 100 μ M; P＜0.05) obtains minimal absorption.Cellular control unit 40 minutes stress during suppress cell expansion, and the cell of handling with compound 2 does not have expansion.
This area common technique personnel can carry out accommodation, change etc. to content described herein, and do not break away from spirit of the present invention and principal character.Therefore, scope of the present invention is not to be defined by aforementioned exemplary explanation institute, but is defined by claims of back literary composition, and is intended to comprise the institute that meets claims equivalence meaning and scope and changes.

Claims (31)

1. the compound of formula III or its pharmacy acceptable salt or hydrate:
Figure FDA0000152435500000011
Wherein:
K is 0,1 or 2,
R 1Be hydrogen,
Y ' is NR 2R 3, R wherein 2Be hydrogen or methyl, R 3Be selected from hydrogen, C 1-10Alkyl, C (O) R 6And C (O) OR 6
R 4Be OH or NH 2,
R 5And R 6Independently be selected from hydrogen and optional substituted C 1-10Alkyl, and
Z is a benzoyl-, and optional by 1-5 Q group replacement, wherein each Q independently is selected from F, Cl, Br, I, C 1-10Alkyl, CF 3, OCF 3, NO 2, O-C 1-10Alkyl, OH, NH 2, NH (C 1-10Alkyl), N (C 1-10Alkyl) 2And NHC (O) C 1-10Alkyl.
2. according to the compound of claim 1, R wherein 3Be hydrogen.
3. according to the compound of claim 1, R wherein 3Be C (O) R 6, and R 6Be hydrogen or optional substituted 1-10Alkyl.
4. according to each compound or its pharmacy acceptable salt or hydrate among the claim 1-3, said compound has following structure:
Figure FDA0000152435500000012
5. according to each compound or its pharmacy acceptable salt or hydrate among the claim 1-3, said compound has following structure:
Figure FDA0000152435500000021
6. according to each compound or its pharmacy acceptable salt or hydrate among the claim 1-3, said compound has following structure:
7. according to each compound or its pharmacy acceptable salt or hydrate among the claim 1-3, said compound has following structure:
Figure FDA0000152435500000023
8. according to compound or its pharmacy acceptable salt or the hydrate of claim 1, said compound is:
1-(2-amino-ethanoyl)-4-(4-nitro-benzoyl-amido)-tetramethyleneimine-2-formic acid;
1-(2-amino-ethanoyl)-4-benzoyl-amido-tetramethyleneimine-2-formic acid;
1-(2-amino-ethanoyl)-4-(4-methyl-benzoyl-amido)-tetramethyleneimine-2-formic acid;
1-(2-amino-ethanoyl)-4-(4-methoxyl group-benzoyl-amido)-tetramethyleneimine-2-formic acid;
1-(2-amino-ethanoyl)-4-(4-hydroxyl-benzoyl-amido)-tetramethyleneimine-2-formic acid;
1-(3-amino-propionyl group)-4-benzoyl-amido-tetramethyleneimine-2-formic acid.
9. according to compound or its pharmacy acceptable salt or the hydrate of claim 1 or 8, said compound is:
(2S, 4R) 1-(2-amino-ethanoyl)-4-(4-nitro-benzoyl-amido)-tetramethyleneimine-2-formic acid;
(2S, 4R) 1-(2-amino-ethanoyl)-4-benzoyl-amido-tetramethyleneimine-2-formic acid;
(2S, 4R) 1-(2-amino-ethanoyl)-4-(4-methyl-benzoyl-amido)-tetramethyleneimine-2-formic acid;
(2S, 4R) 1-(2-amino-ethanoyl)-4-(4-methoxyl group-benzoyl-amido)-tetramethyleneimine-2-formic acid;
(2S, 4R) 1-(2-amino-ethanoyl)-4-(4-hydroxyl-benzoyl-amido)-tetramethyleneimine-2-formic acid;
(2S, 4R) 1-(3-amino-propionyl group)-4-benzoyl-amido-tetramethyleneimine-2-formic acid.
10. according to compound or its pharmacy acceptable salt or the hydrate of claim 1, said compound is:
1-(2-glycyl)-4-benzamido-pyrrolidone-2-methane amide;
1-(2-glycyl)-4-benzamido--N-methylpyrrolidin-2-methane amide;
1-(2-glycyl)-4-benzamido--N-ethyl pyrrolidine-2-methane amide;
1-(2-glycyl)-4-benzamido--N-sec.-propyl tetramethyleneimine-2-methane amide;
1-(2-glycyl)-4-benzamido--N-cyclopropyl tetramethyleneimine-2-methane amide;
4-benzamido--1-(2-(tert-butoxycarbonyl is amino) ethanoyl) tetramethyleneimine-2-methane amide;
1-(2-glycyl)-4-benzamido--N-(penta-3-yl) tetramethyleneimine-2-methane amide;
1-(2-glycyl)-4-benzamido--N-cyclopentyl tetramethyleneimine-2-methane amide;
1-(2-glycyl)-4-benzamido--N-isobutyl-tetramethyleneimine-2-methane amide;
1-(2-glycyl)-4-benzamido--N-cyclobutyl tetramethyleneimine-2-methane amide;
1-(2-glycyl)-4-benzamido--N-tertiary butyl tetramethyleneimine-2-methane amide;
1-(2-glycyl)-4-benzamido--N-(3-methyl fourth-2-yl) tetramethyleneimine-2-methane amide;
1-(2-glycyl)-4-benzamido--N-(3,3-dimethyl butyrate-2-yl) tetramethyleneimine-2-methane amide.
11. according to compound or its pharmacy acceptable salt or the hydrate of claim 1 or 10, said compound is:
(2S, 4R) 1-(2-glycyl)-4-benzamido-tetramethyleneimine-2-methane amide;
(2S, 4R) 1-(2-glycyl)-4-benzamido--N-methylpyrrolidin-2-methane amide;
(2S, 4R) 1-(2-glycyl)-4-benzamido--N-ethyl pyrrolidine-2-methane amide;
(2S, 4R) 1-(2-glycyl)-4-benzamido--N-sec.-propyl tetramethyleneimine-2-methane amide;
(2S, 4R) 1-(2-glycyl)-4-benzamido--N-cyclopropyl tetramethyleneimine-2-methane amide;
(2S, 4R) 4-benzamido--1-(2-(tert-butoxycarbonyl is amino) ethanoyl) tetramethyleneimine-2-methane amide;
(2S, 4R) 1-(2-glycyl)-4-benzamido--N-(penta-3-yl) tetramethyleneimine-2-methane amide;
(2S, 4R) 1-(2-glycyl)-4-benzamido--N-cyclopentyl tetramethyleneimine-2-methane amide;
(2S, 4R) 1-(2-glycyl)-4-benzamido--N-isobutyl-tetramethyleneimine-2-methane amide;
(2S, 4R) 1-(2-glycyl)-4-benzamido--N-cyclobutyl tetramethyleneimine-2-methane amide;
(2S, 4R) 1-(2-glycyl)-4-benzamido--N-tertiary butyl tetramethyleneimine-2-methane amide;
(2S, 4R) 1-(2-glycyl)-4-benzamido--N-(3-methyl fourth-2-yl) tetramethyleneimine-2-methane amide;
(2S, 4R) 1-(2-glycyl)-4-benzamido--N-(3,3-dimethyl butyrate-2-yl) tetramethyleneimine-2-methane amide.
12. according to compound or its pharmacy acceptable salt or the hydrate of claim 1, said compound is:
1-(2-kharophen ethanoyl)-4-benzamido-tetramethyleneimine-2-formic acid;
4-benzamido--1-(2-(methylamino) ethanoyl)-tetramethyleneimine-2-formic acid;
4-benzamido--1-(2-(2,2, the 2-trifluoroacetamido) ethanoyl) tetramethyleneimine-2-formic acid;
4-benzamido--1-(2-(tert-butoxycarbonyl is amino) ethanoyl) tetramethyleneimine-2-formic acid;
4-benzamido--1-(2-dimethylamino) acetyl-pyrrolidine-2-formic acid;
4-benzamido--1-(2-formamido group ethanoyl) tetramethyleneimine-2-formic acid.
13. according to compound or its pharmacy acceptable salt or the hydrate of claim 1 or 12, said compound is:
(2S, 4R) 1-(2-kharophen ethanoyl)-4-benzamido-tetramethyleneimine-2-formic acid;
(2S, 4R) 4-benzamido--1-(2-(methylamino) ethanoyl)-tetramethyleneimine-2-formic acid;
(2S, 4R) 4-benzamido--1-(2-(2,2, the 2-trifluoroacetamido) ethanoyl) tetramethyleneimine-2-formic acid;
(2S, 4R) 4-benzamido--1-(2-(tert-butoxycarbonyl is amino) ethanoyl) tetramethyleneimine-2-formic acid; Or
(2S, 4R) 4-benzamido--1-(2-dimethylamino) acetyl-pyrrolidine-2-formic acid;
(2S, 4R) 4-benzamido--1-(2-formamido group ethanoyl) tetramethyleneimine-2-formic acid.
14. according to compound or its pharmacy acceptable salt or the hydrate of claim 1, said compound is 1-(2-amino-ethanoyl)-4-benzoyl-amido-tetramethyleneimine-2-formic acid.
15. according to compound or its pharmacy acceptable salt or the hydrate of claim 14, said compound is (2S, 4R) 1-(2-amino-ethanoyl)-4-benzoyl-amido-tetramethyleneimine-2-formic acid.
16. pharmaceutical composition, this pharmaceutical composition comprise according to each compound or its pharmacy acceptable salt or hydrate and pharmaceutically acceptable carrier among the claim 1-15.
17., be used for treatment according to each compound among the claim 1-15.
18. according to each compound among the claim 1-15, be used for treating or preventing the method for pathological condition, said pathological condition is selected from cardiovascular disorder; Osteoporosis; The airway epithelial inflammation; The honeycomb weave illness; Bladder incontinence; Hearing loss; The endothelium pathology; I type or type ii diabetes; Diabetic retinopathy; Diabetic neuropathy; Atherosclerosis; The disease relevant with CNS; Epileptic seizures; Local asphyxia; The dental tissue illness; Kidney disease; Anaemia; Leukopenia; Thrombocytopenia; Pancytopenia; The appearance wound; Because what wound caused gos deep into wound; Fracture; Erection problem; The urine bladder incontinence; Neuropathic pain; Inferior chronic and chronic inflammatory diseases; Cancer; The bone marrow transplantation failure; The stem cell transplantation failure; The situation that during cell and tissue transplantation, takes place; The patient's condition in the operating period generation of medical journey; The patient's condition that is caused because of excess reactivity oxygen species, radical or nitrogen protoxide; Conceived disease or illness; Infertility, and apoplexy.
19. be used for the prevention of claim 18 or the compound of method of treatment pathological condition, said pathological condition is a local asphyxia.
20. be used for the prevention of claim 18 or the compound of method of treatment pathological condition, said pathological condition is a cardiovascular disorder.
21. be used for the prevention of claim 20 or the compound of method of treatment pathological condition, said cardiovascular disorder is atrial fibrillation, auricular flutter, ventricular tachycardia or ventricular fibrillation.
22., be used for method in one or more mammalian organs preventions or the damage of treatment local asphyxia according to each compound among the claim 1-15.
23. according to the compound of claim 22, wherein said organ is selected from heart, cns, kidney, gi tract, liver, lung and four limbs.
24. be used for each prevention or the compound of method of treatment pathological condition of claim 18-23, wherein said compound through preparation for parenteral or oral administration.
25. according to the purposes that each compound among the claim 1-15 is used for treating or preventing the medicine of pathological condition in preparation, said pathological condition is selected from cardiovascular disorder; Osteoporosis; The airway epithelial inflammation; The honeycomb weave illness; Bladder incontinence; Hearing loss; The endothelium pathology; I type or type ii diabetes; Diabetic retinopathy; Diabetic neuropathy; Atherosclerosis; The disease relevant with CNS; Epileptic seizures; Local asphyxia; The dental tissue illness; Kidney disease; Anaemia; Leukopenia; Thrombocytopenia; Pancytopenia; The appearance wound; Because what wound caused gos deep into wound; Fracture; Erection problem; The urine bladder incontinence; Neuropathic pain; Inferior chronic and chronic inflammatory diseases; Cancer; The bone marrow transplantation failure; The stem cell transplantation failure; The situation that during cell and tissue transplantation, takes place; The patient's condition in the operating period generation of medical journey; The patient's condition that is caused because of excess reactivity oxygen species, radical or nitrogen protoxide; Conceived disease or illness; Infertility, and apoplexy.
26. the purposes of claim 25, wherein said pathological condition are local asphyxia.
27. the purposes of claim 26, wherein said pathological condition are cardiovascular disorder.
28. the purposes of claim 27, wherein said cardiovascular disorder are atrial fibrillation, auricular flutter, ventricular tachycardia or ventricular fibrillation.
29. be used for purposes in preparation at the medicine of one or more mammalian organs preventions or the damage of treatment local asphyxia according to each compound among the claim 1-15.
30. the purposes of claim 29, wherein said organ is selected from heart, cns, kidney, gi tract, liver, lung and four limbs.
31. each purposes among the claim 26-30, wherein said compound is through preparing for parenteral or oral administration.
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